Pyrrolopyrimidinone derivatives, process of preparation and use

ABSTRACT

The invention relates to a series of pyrrolopyrimidinone derivatives of the formula (1), processes for their preparation, intermediates in their preparation, their use as therapeutic agents, and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention relates to a series of pyrrolopyrimidinonederivatives of the formula (1), processes for their preparation,intermediates in their preparation, their use as therapeutic agents, andpharmaceutical compositions containing them,

[0003] wherein R¹ is H; C₁-C₃ alkyl optionally substituted with one ormore fluoro atoms; or C₃-C₆ cycloalkyl;

[0004] R² is H; a halogen atom; C₁-C₆ alkyl optionally substituted withOH, C₁-C₃ alkoxy, C₃-C₆ cycloalkyl, or with one or more fluoro atoms;C₃-C₆ cycloalkyl; C₂-C₆ alkenyl; or C₂-C₆ alkynyl;

[0005] R³ is H; C₁-C₆ alkyl optionally substituted with OH, C₁-C₃alkoxy, C₃-C₆ cycloalkyl, or with one or more fluoro atoms; C₃-C₆cycloalkyl; C₂-C₆ alkenyl; or C₂-C₆ alkynyl;

[0006] R⁴ is C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl orwith one or more fluoro atoms; C₂-C₆ alkenyl; C₂-C₆ alkynyl; or C₃-C₆cycloalkyl;

[0007] R⁵ is SO₂NR⁶R⁷; NHSO₂NR⁶R⁷; NHCOCONR(R⁶R⁷; NHSO₂R⁸; NHCOR⁸: orphenyl or heterocyclyl either of which is optionally substituted withone or more fluoro atoms or C₁-C₃ alkyl;

[0008] R⁶ and R⁷ are each independently H or C₁-C₆ alkyl optionallysubstituted with OH, CO₂H, C₁-C₃ alkoxy, C₃-C₆ cycloalkyl, or with oneor more fluoro atoms; or together with the nitrogen atom to which theyare attached form either a mono-cyclic ring such as imidazole, aziridene(aziridine), azeridine (azetidine), pyrrolidine, piperidine, morpholine,piperazine and homopiperazine, or a bicyclic ring such as2,5-diazabicyclo[2.2.1]heptane and 3,7-diazabicyclo[3.3.0]octane,wherein said group is optionally substituted with R⁹;

[0009] R⁸ is C₁-C₆ alkyl optionally substituted with one or more fluoroatoms; or C₃-C₇ cycloalkyl;

[0010] R⁹ is C₁-C₆ alkyl optionally substituted with one or more halideatoms, OH, C₁-C₃ alkoxy which is optionally substituted with one or morefluoro atoms, CO₂R¹⁰, NR¹¹R¹², C═NR¹³(NR¹⁴R¹⁵), or with a tetrazolegroup which is optionally substituted with C₁-C₃ alkyl; or one or morenitrogen containing heteroaryl group which is optionally substitutedwith one or more fluoro atoms;

[0011] R¹⁰ is H; or C₁-C₄ alkyl optionally substituted with OH, NR¹¹R¹²,one or more fluoro atoms, or with a nitrogen containing heterocyclicring such as pyrrolidine, piperidine, piperazine, morpholine, pyrrole,and imidazole wherein nitrogen atom is directly bound to C₁-C₄ alkyl;

[0012] R¹¹ and R¹² are each independently H or C₁-C₄ alkyl;

[0013] R¹³ is H; C₁-C₄ alkyl optionally substituted with one or morefluoro atoms; or C₃-C₆ cycloalkyl;

[0014] R¹⁴ and R¹⁵ are each independently H or C₁-C₄ alkyl optionallysubstituted with one or more fluoro atoms; C₃-C₆ cycloalkyl; or togetherwith the nitrogen atom to which they are attached from a pyrrolidinylpiperidino, morpholino, piperazinyl, or homopiperazinyl group whereinsaid group is optionally substituted with C₁-C₃ alkyl.

[0015] 2. Description of the Prior Art

[0016] European patent applications EP-A-0463756 and EP-A-0526004disclose certain pyrazolo [4,3-d]pyrimidin-7-ones as cGMP PDEinhibitors, useful in the treatment of cardiovascular disorders such asangina, hypertension and heart failure. International application WO94/28902 discloses their use for the treatment of impotence.

[0017] The present inventors have recently disclosed a series ofpyrazolo[4,3-d]pyrimidin-7-one derivatives as PDE V inhibitors (Appln.No. KR 98-60436 and KR 99-7580). Herein a new series ofpyrrolo[4,33,2d]-pyrimidin-74-one derivatives are prepared as PDE Vinhibitors. However, none of the compounds of this invention arespecifically disclosed.

SUMMARY OF THE INVENTION

[0018] The compounds (1) of this invention are potent and selectiveinhibitors of cyclic guanosine 3′,5′-monophosphate specificphosphodiesterase (cGMP specific PDE; PDE V) having utility in a varietyof therapeutic areas where such inhibition is thought to be beneficial,including the treatment of impotence (male erectile dysfunction), sexualdysfunction in female, and various cardiovascular disorders such asangina, hypertension, heart failure and atherosclerosis.

[0019] As a consequence of the selective PDE V inhibition exhibited bycompounds of this invention, cGMP levels are elevated, which in turn cangive rise to beneficial vasodilatory, anti-vasospastic, anti-platelet,anti-neutrophil, natriuretic and diuretic activities as well aspotentiation of the effects of endothelium-derived relaxing factor(EDRF), nitrovasodilators, atrial natriuretic factor (ANF), brainnatriuretic peptide (BNP), C-type natriuretic peptide (CNP) andendothelium-dependent relaxing agents such as bradykinin, acetylcholineand 5-HT₁.

[0020] The compounds of this invention therefore have utility in thetreatment of a number of disorders, including impotence, sexualdysfunction in female, stable, unstable and variant (Prinzmetal) angina,hypertension, pulmonary hypertension, congestive heart failure, renalfailure, atherosclerosis, conditions of reduced blood vessel patency(e.g. post-percutaneous transluminal coronary angioplasty), peripheralvascular disease, vascular disorders such as Raynaud's disease,inflammatory diseases, stroke, bronchitis, chronic asthma, allergicasthma, allergic rhinitis, glaucoma and diseases characterized bydisorders of gut motility (e.g. irritable bowel syndrome).

DETAILED DESCRIPTION OF THE INVENTION

[0021] Thus, according to a first aspect, this invention providescompounds of the formula (1) and pharmaceutically acceptable salts andsolvates (e.g. hydrates) thereof,

[0022] wherein R¹, R², R³, R⁴ and R⁵ are as previously defined.

[0023] In the above definition, unless otherwise indicated, alkyl groupshaving three or more carbon atoms may be straight or branched chain. Inaddition, alkenyl or alkynyl groups having four or more carbon atoms, oralkoxy groups having three carbon atoms, may be straight or branchedchain.

[0024] Compounds of the formula (1) may contain one or more asymmetriccenters and thus can exist as enantiomers or diastereomers. It is to beunderstood that the invention includes both mixtures and separateindividual isomers of compounds of the formula (1). Furthermore certaincompounds of the formula (1) which contain alkenyl groups may exist ascis- or trans-isomers. In each instance, the invention includes bothmixtures and separate individual isomers.

[0025] Compounds of the formula (1) may also exist in tautomeric formsand the invention includes both mixtures and separate individualtautomers thereof.

[0026] Also included in the invention are radiolabelled derivatives ofcompounds of formula (1) which are suitable for biological studies.

[0027] Compounds of the formula (1) wherein one or more basic nitrogenatoms are present may form pharmaceutically acceptable salts with acidssuch as hydrochloric, hydrobromic, sulfuric, phosphoric,methanesulfonic, acetic, citric, fumaric, lactic, maleic, succinic andtartaric acids.

[0028] Compounds of the formula (1) may form pharmaceutically acceptablesalts with metal ions, such as alkali metals for example sodium andpotassium, or with an ammonium ion.

[0029] A preferred group of compounds of the formula (1) is that

[0030] wherein

[0031] R¹ is H; methyl; or ethyl;

[0032] R² is H; methyl; or a halogen atom;

[0033] R³ is C₁-C₄ alkyl optionally substituted with one or more fluoroatoms;

[0034] R⁴ is ethyl; n-propyl; or allyl;

[0035] R⁵ is SO₂NR⁶R⁷; or NHSO₂R⁸;

[0036] R⁶ and R⁷ taken together with the nitrogen atom to which they areattached form a piperidino, piperazinyl or homopiperazinyl group whereinsaid group is substituted with R⁹;

[0037] R⁸ is methyl;

[0038] R⁹ is C₁-C₄ alkyl optionally substituted with one or more halideatoms, OH, CO₂R¹⁰, or with a tetrazole group which is optionallysubstituted with C₁-C₃ alkyl; R¹⁰ is H.

[0039] A particularly preferred group of compounds of the formula (1) isthat wherein

[0040] R¹ is methyl; or ethyl;

[0041] R² is H;

[0042] R³ is ethyl; n-propyl; 3-fluoropropyl; or cyclopropylmethyl;

[0043] R⁴ is ethyl; or n-propyl;

[0044] R⁵ is SO₂NR⁶R⁷; or NHSO₂R⁸;

[0045] R⁶ and R⁷ taken together with the nitrogen atom to which they areattached form a piperidino or piperazinyl group wherein said group issubstituted with R⁹,

[0046] R⁸ is methyl;

[0047] R⁹ is C₁-C₄ alkyl optionally substituted with one or more fluoroor chloro atoms, OH, CO₂R¹⁰, or with a tetrazole group;

[0048] R¹⁰ is H.

[0049] Especially preferred individual compounds of the inventioninclude:

[0050]52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0051]52-(5-(4-methylpipiperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2,-d]pyrimidin-74-one;

[0052]52-(2-ethoxy-5-(4-n-propylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0053]52-(2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1-ylsulfonyl)phenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2d]-pyrimidin-74-one;

[0054]52-(2-ethoxy-5-(4-(2-fluoroethyl)piperazinylpiperazin-1ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0055]52-(5-(4-(2-fluoroethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0056]52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-5-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0057]52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-37-ethyl-15-methyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0058]52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-37-(3-fluoropropyl)-15-methyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0059]37-cyclopropylmethyl-52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0060]52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-ethyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0061]52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0062]52-(2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0063]52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0064]52-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0065]52-(2-ethoxy-5-(4-ethylpiperazinylpiperazin-1-ylsulfonyl)phenyl)15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0066]52-(5-(4-ethylpiperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0067]52-(2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin74-one;

[0068]52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0069]52-(5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[(4,33,2-d]pyrimidin-74-one;

[0070]52-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0071]52-(5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0072]52-(5-(4-(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[4.33,2-d]pyrimidin-74-one;

[0073]2-(5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;

[0074]52-(5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0075]52-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one,

[0076]52-(5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74one;

[0077]52-(5-(2-ethoxy-4(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0078]52-(5-(4-(3-hydroxypropylpiperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0079]52-(5-(4-(hydroxycarbonylmethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin74-one;

[0080]52-(5-(4-(hydroxycarbonylmethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0081]52-(2-ethoxy-5-(4-(2-hydroxycarbonylethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0082]52-(5-(4-(2-hydroxycarbonylethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0083]52-(2-ethoxy-5-(4-(1H-tetrazol-5-ylmethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0084]15-methyl-52-(2-n-propoxy-5-(4-(2-(1H-tetrazol-5-yl)ethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0085]52(2-ethoxy-5-(4-(1h-tetrazol-5-ylmethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0086]15-methyl-52-(2-n-propoxy-5-(4-(1-tetrazol-5-ylmethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one;

[0087] and physiologically acceptable salts and solvates (e.g. hydrates)thereof.

[0088] In another aspect, this invention provides processes for thepreparation of compounds of the formula (1) or pharmaceuticallyacceptable salts thereof. Compounds of the formula (1) may be preparedfrom compounds of the formula (2), (3) or (4):

[0089] wherein R¹, R², R³ and R⁴ are as previously defined, and Xrepresents sulfonyl halide, cyano or amino group, and Y represents ahalogen atom, preferably a chloro atom. The coupling reaction ofcompounds of the formula (2) with a compound of the formula (5) (whereinR⁶ and R⁷ are as previously defined) is generally carried out at 0° C.to room temperature for 1-24 hours in a suitable solvent such as a C₁-C₃alkanol, dichloromethane, DMF, or water using an excess amount of (5) orin the presence of an organic tertiary amine, preferably triethylamineto scavenge the acid by-product. For Compounds of the formula (1)wherein R⁹ is C₁-C₆ alkyl substituted with C═NR¹³(NR¹⁴R¹⁵), a cyanogroup in the precursor compound may be transformed into the amidinefunctionality. The reaction can he affected by treating a cyano compoundwith saturated HCl gas in an anhydrous alcohol such as methanol andethanol, at −20° to 0° C., and the subsequent reaction of the resultingalkyl imidate intermediate with an appropriate amine at 0° C. to roomtemperature.

[0090] The reaction of amine compounds of the formula (3) with acompound of the formula (6), (7) or (8):

[0091] (wherein R⁸ is as previously defined, and Y represents a halogenatom, preferably a chloro atom) is conveniently carried out at 0° C. toroom temperature for 1-24 hours in an inert anhydrous solvent such asdichloromethane or THF using an excess amount of (6), (7) or (8), in thepresence of an organic tertiary amine, preferably triethylamine toscavenge the acid by-product. The sulfonyl halide of the formula (6),the carboxylic acid anhydride of the formula (7) and the acyl halide ofthe formula (8) are either commercially available or readily obtainableby conventional synthetic procedures.

[0092] The cyano compounds of the formula (4) can be effectivelyconverted to the corresponding tetrazole derivatives by reacting withNaN₃ in the presence of n-Bu₃SnCl as a Lewis acid at refluxingtemperature in an anhydrous hydrocarbon solvent such as toluene.

[0093] Compounds of the formula (2), (3) and (4) may be prepared fromcompounds of the formula (9), (10) and (11), respectively:

[0094] (wherein R¹, R², R³ and R⁴ are as previously defined, and Xrepresents hydrogen, nitro or bromide group) by adopting precedentprocedures.

[0095] Compounds of the formula (2) may be prepared from compounds ofthe formula (9) by using known methods for the introduction of asulfonyl halide group into an aromatic ring, for example, when haliderepresents a chloro atom, by the action of chlorosulfonic acid at 0° C.to room temperature for 3-24 hours without any solvent.

[0096] The amines of the formula (3) can be readily obtained byreduction of the corresponding nitro compounds of the formula (10) usingwell-known methods such as catalytic hydrogenation in an alcoholicsolvent, or tin (II) chloride reduction, and so on.

[0097] The cyano compounds of the formula (4) may be readily preparedfrom the bromide compounds of the formula (11) by displacement of thebromide with CuCN at 150-200° C. in a high boiling solvent such as1-methyl-2-pyrrolidinone.

[0098] Compounds of the formula (9), (10) and (11) may be prepared fromcompounds of the formula (12), (13) and (14), respectively:

[0099] (wherein R¹, R², R³ and R⁴ are as previously defined, and Xrepresents hydrogen, nitro or bromide group) by the application of knowncyclization methods for pyrimidinone ring formation.

[0100] A cyclization reaction is generally carried out by heating at anelevated temperature, for example 50-150° C., in the presence of an acidor a base in a suitable solvent such as an aqueous C₁-C₄ alkanol, water,a halogenated hydrocarbon, or acetonitrile. Thus, for example, thecyclization may be affected by treatment of a compound of the formulae(12)-(14) with all inorganic or organic base such as sodium hydroxide,potassium carbonate or potassium tert-butoxide, in an alcoholic aqueousmedium, preferably potassium tert-butoxide in tert-butanol at 60° C. toreflux temperature.

[0101] For compounds of the formula (9) (wherein R¹, R³ and R⁴ are aspreviously defined, and R² is halide), the introduction of a halide atomto compounds of the formula (12) is carried out prior to subsequentcyclization. Halogenations may be affected by applying appropriateconditions for each halide, for example, N-chlorosuccinimide (NCS) in ahalogenated solvent such as CH₂Cl₂ at −10° C. to room temperature forchlorination, bromine in acetic acid in the presence of sodium acetateat room temperature for bromination, and iodine along with mercuricoxide (HgO) in a hydrocarbon solvent such as benzene at 0° C. to roomtemperature for iodination.

[0102] Compounds of the formulae (12)-(14) may be prepared fromcompounds of the formula (15) and (16), (17) or (18), respectively:

[0103] wherein R¹, R², R³ and R⁴ are as previously defined, X representshydrogen, nitro or bromide group and Y represents a hydroxyl group or ahalogen atom, preferably a chloro atom.

[0104] The reaction is generally carried out by first converting acarboxylic acid of the formulae (16)-(18) (Y═OH) to the correspondingacyl chloride using excess amounts of well-known reagents in theliterature, preferably thionyl chloride or oxalyl chloride, in thepresence of an inert solvent such as dichloromethane or benzene at roomtemperature to reflux temperature. The coupling reaction with a compoundof the formula (15) is generally affected by using an excess of theresulting acyl chloride (16)-(18) (Y═Cl) in the presence of an excess ofan organic tertiary amine such as triethylamine to act as scavenger forthe acid by-product (HY), optionally in the presence of a catalyst suchas 4-dimethylaminopyridine (DMAP), in an inert anhydrous solvent such asdichloromethane at 0° C. to room temperature for 2-6 hours. The startingmaterials of the formulae (16)-(18) (Y═OH) are either commerciallyavailable or readily obtainable from the compound of the formula (16) bythe methods known in the literature. For example, the nitro compounds ofthe formula (17) can be efficiently prepared from compounds of theformula (16) by using known methods for the nitration of an aromaticring, and the reaction is generally carried out using sodium nitrite orfuming nitric acid under a strongly acidic medium such as concentratedsulfuric acid or trifluoroacetic acid, preferably trifluoroacetic acid,at −10° C. to room temperature for 1-24 hours.

[0105] Compounds of the formula (15) may be prepared from compounds ofthe formula (20) in two steps:

[0106] (wherein R¹, R² and R³ are as previously defined) by convertingcompounds of the formula (20) into the corresponding amide compounds ofthe formula (19) and the subsequent cyclization of compounds of theformula (19) for pyrrole ring formation. Amide formation may be affectedby using ammonia either in an alcoholic solvent or water, preferablywater, at room temperature to 100° C., in the presence or absence ofsodium cyanide as a catalyst.

[0107] A cyclization reaction is effectively carried out by heating atan elevated temperature for example 50-150° C., in the presence of abase in a suitable solvent such as aqueous C₁-C₄ alkanol oracetonitrile. Thus, for example, the cyclization may be affected bytreatment of a compound of the formula (20) with an alkoxide base suchas sodium ethoxide or potassium tert-butoxide, in an alcoholic medium.preferably sodium ethoxide in ethanol at 60° C.

[0108] Compounds of the formula (20) may be prepared from compounds ofthe formula (21) and (22):

[0109] wherein R¹, R² and R³ are as previously defined.

[0110] A condensation reaction between compounds of the formula (21) and(22) is generally performed in a mixture of an alcohol and water,preferably methanol alone, in the presence of a weak base such as sodiumacetate, at room temperature for 1-3 days. Compounds of the formula (21)are either commercially available or readily obtainable from glycineusing well-documented synthetic methods.

[0111] Compounds of the formula (22) may be prepared from compounds ofthe formula (23) and (24):

[0112] wherein R² and R³ are as previously defined, and R is C₁-C₃alkyl.

[0113] Acylation reaction of compounds of the formula (23) isefficiently carried out by trapping the anionic species of compounds ofthe formula (23) with compounds of the formula (24) at −78° C. to roomtemperature. Generation of the anionic intermediate from compounds ofthe formula (23) may be affected by the action of a strong amide basesuch as sodium amide, alkali metal hexamethyldisilazide (Li, Na, orKHMDS) or lithium diisopropylamide (LDA), preferably LDA, in ananhydrous ethereal solvent such as tetrahydrofuran, at low temperature,ranging from −78° to 0° C.

[0114] Compounds of the formula (1) may be also prepared by cyclizingcompounds of the formula (25):

[0115] wherein R¹, R², R³ and R⁴ are as previously defined, and R¹⁶ is agroup R⁵ as hereinbefore defined or a precursor to a group R⁵.

[0116] A cyclization reaction is generally carried out by heating at anelevated temperature, for example 50-150° C., in the presence of an acidor a base in a suitable solvent such as an aqueous C₁-C₄ alkanol, water,a halogenated hydrocarbon, or acetonitrile. Thus, for example, thecyclization may be affected by treatment of a compound of the formula(25) with an inorganic or organic base such as sodium hydroxide,potassium carbonate or potassium tert-butoxide, in an aqueous alcoholicmedium. Examples of R¹⁶ being a precursor to a group R⁵ are when R⁵contains a carboxylic acid since an ester group of the formula (25) canbe converted to the corresponding carboxylic acid under the basiccyclization condition.

[0117] Compounds of the formula (25) may be prepared from compounds ofthe formula (15) and (26):

[0118] wherein R¹, R², R³, R⁴ and R¹⁶ are as previously defined, and Yrepresents a hydroxyl group or a halogen atom, preferably a chloro atom.

[0119] The reaction is generally carried out by first converting acarboxylic acid of the formula (26) (Y═OH) to the corresponding acylchloride using excess amounts of well-known reagents in the literature,preferably thionyl chloride or oxalyl chloride, in the presence orabsence of an inert solvent such as dichloromethane or benzene, at roomtemperature to reflux temperature. The coupling reaction with a compoundof the formula (15) is generally affected by using an excess of theresulting acyl chloride (26) (Y═Cl) in the presence of an excess of anorganic tertiary amine such as triethylamine to act as scavenger for theacid by-product (HY), optionally in the presence of a catalyst such as4-dimethylaminopyridine (DMAP), in an inert anhydrous solvent such asdichloromethane at 0° C. to room temperature for 2-6 hours. The startingmaterials of the formula (26) (Y═OH) are readily obtainable fromcompound of the formula (16) (X═H, Y═OH) by the methods known in theliterature.

[0120] Amines of the formula (5)(5a), when not commercially available,can be prepared by conventional synthetic procedures, in accordance withliterature precedents, from readily accessible starting materials usingstandard reagents and reaction conditions.

[0121] Certain compounds of the formula (5), (5a), wherein R⁶ and R⁷taken together with the nitrogen atom to which they are attached form apiperazinyl or homopiperazinyl group substituted with R⁹ (R⁹ is aspreviously defined), can be synthesized readily from the compounds ofthe formula (27):

[0122] wherein Z is a group CF₃, hydroxyl, or a halogen, preferablyfluoro atom and P represents an appropriate protecting group, forexample, benzyl, benzyloxycarbonyl (Cbz) or tert-butoxycarbonyl (Boc).

[0123] Removal of benzyl or benzyloxycarbonyl (Cbz) group in thecompounds of the formula (27) can be performed under a hydrogenationcondition using a catalytic amount of palladium on carbon in analcoholic solvent such as methanol or ethanol, at room temperature toafford the corresponding compound of the formula (5a). Cleavage oftert-butoxycarbonyl (Boc) group in the compounds of the formula (27) canbe affected under the acidic conditions using aqueous HCl ortrifluoroacetic acid in an aprotic solvent such as tetrahydrofuran ordichloromethane at room temperature to afford the corresponding salt ofthe formula (5a). Starting materials of the formula (27) can be preparedfrom 1-benzylpiperazine or 1-tert-butoxycarbonylhomepiperazine of theformula (28) by direct N-alkylation with an appropriate alkyl halidecontaining a CF₃, hydroxyl or halogen group.

[0124] Another compounds of the formula (5), (5b), wherein R⁶ and R⁷taken together with the nitrogen atom to which they are attached form apiperazinyl or piperidino group substituted with R⁹ (R⁹ is as previouslydefined and is substituted with a 1H-(tetrazol-5-yl) group), can besynthesized readily from the compounds of the formula (29):

[0125] wherein X is a group methine or nitrogen atom and P represents anappropriate protecting group, for example, preferablytert-butoxycarbonyl (Boc).

[0126] Removal of tert-butoxycarbonyl (Boc) and triphenylmethyl (Trityl)groups in the compounds of the formula (29) can be affectedsimultaneously under the acidic conditions using aqueous HCl ortrifluoroacetic acid in an aprotic solvent such as tetrahydrofuran atroom temperature, in the presence of excess 1H-tetrazole as acarbocation scavenger, to afford the corresponding salt of the formula(5b).

[0127] Compounds of the formula (29) can be prepared from the compoundsof the formula (30):

[0128] wherein X and P are as previously defined.

[0129] Conversion of the cyano group of the formula (30) is generallyaffected by using tributyltin chloride and sodium azide in a hydrocarbonsolvent, preferably toluene, at refluxing temperature to affordcorresponding tetrazole compounds of the formula (29). Compounds of theformula (30) are readily prepared either from1-tert-butoxycarbonylpiperazine of the formula (31) by directN-alkylation with an appropriate alkyl halide containing a cyano group,or by conversion of the hydroxyl functionality of the formula (32) to acyano group, using well-documented procedures. Starting materials of theformula (31) and (32) are either commercially available or readilyaccessible by conventional synthetic procedures in accordance withliterature precedents.

[0130] The resulting compounds of this invention represented by theformula (1)-(5), (9)-(15) and (19)-(22), can be separated and purifiedby appropriate conventional methods such as column chromatography andrecrystallization.

[0131] Compounds of the invention may be administered by any suitableroute, for example by oral, buccal, sub-lingual, rectal, vaginal, nasal,topical or parenteral (including intravenous, intramuscular,subcutaneous and intracoronary) administration.

[0132] For administration to man in the curative or prophylactictreatment of the disorders identified above, oral, buccal or sub-lingualdosages of a compound of the formula (1) will generally be in the rangeof from 0.1-400 mg daily for an average adult patient (70 Kg). Thus fora typical adult patient, individual tablets or capsules contain from0.05-200 mg of active compound, in a suitable pharmaceuticallyacceptable vehicle or carrier, for administration in single or multipledoses, once or several times per day. Dosages for parenteraladministration will typically be within the range of from 0.01-100 mgper single dose as required. In practice the physician will determinethe actual dosing regimen which will be most suitable for an individualpatient and it will vary with the age, weight and response of theparticular patient. The above dosages are exemplary of the average casebut there can be individual instances in which higher or lower dosageranges may be merited, and such are within the scope of this invention.

[0133] For human use, a compound of the formula (1) can be administeredalone, but will generally be administered in admixture with apharmaceutical carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice. For example, thecompound may be administered orally, buccally or sublingually, in theform of tablets containing excipients such as starch or lactose, or incapsules or ovules either alone or in admixture with excipients, or inthe form of elixirs or suspensions containing flavouring or colouringagents. Such liquid preparations may be prepared with pharmaceuticallyacceptable additives such as suspending agent (e.g. methylcellulose, asemi-synthetic glyceride such as witepsol or mixtures of glycerides suchas a mixture of apricot kernel oil and PEG-6 esters or mixtures of PEG-8and caprylic/capric glycerides). A compound may also be injectedparenterally, for example intravenously, intramuscularly, subcutaneouslyor intracoronarily. For parenteral administration, the compound is bestused in the form of a sterile aqueous solution which may contain othersubstances, for example salts, or monosaccharides such as mannitol orglucose, to make the solution isotonic with blood.

[0134] Thus, the invention provides in a further aspect a pharmaceuticalcomposition comprising a compound of the formula (1), or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable diluent or carrier therefor.

[0135] The invention also provides a compound of the formula (1), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition containing either entity, for use in the treatment ofimpotence, sexual dysfunction in female, stable, unstable and variant(Prinzmetal) angina, hypertension, pulmonary hypertension, congestiveheart failure, renal failure, atherosclerosis, conditions of reducedblood vessel patency (e.g. post-percutaneous transluminal coronaryangioplasty), peripheral vascular disease, vascular disorders such asRaynaud's disease, inflammatory diseases, stroke, bronchitis, chronicasthma, allergic asthma, allergic rhinitis, glaucoma and diseasescharacterized by disorders of gut motility (e.g. irritable bowelsyndrome).

[0136] The invention further provides the use of a compound of theformula (1), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition containing either entity, for the manufactureof a medicament for the treatment of impotence, sexual dysfunction infemale, stable, unstable and variant (Prinzmetal) angina, hypertension,pulmonary hypertension, congestive heart failure, renal failure,atherosclerosis, conditions of reduced blood vessel patency (e.g.post-percutaneous transluminal coronary angioplasty), peripheralvascular disease, vascular disorders such as Raynaud's disease,inflammatory diseases, stroke, bronchitis, chronic asthma, allergicasthma, allergic rhinitis, glaucoma and diseases characterized bydisorders of gut motility (e.g. irritable bowel syndrome).

[0137] In a further aspect, the invention provides a method of treatingor preventing impotence, sexual dysfunction in female, stable, unstableand variant (Prinzmetal) angina, hypertension, pulmonary hypertension,congestive heart failure, renal failure, atherosclerosis, conditions ofreduced blood vessel patency (e.g. post-percutaneous transluminalcoronary angioplasty), peripheral vascular disease, vascular disorderssuch as Raynaud's disease, inflammatory diseases, stroke, bronchitis,chronic asthma, allergic asthma, allergic rhinitis, glaucoma anddiseases characterized by disorders of gut motility (e.g. irritablebowel syndrome), in a mammal (including a human being), which comprisesadministering to said mammal a therapeutically effective amount of acompound of formula (1), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition containing either entity.

[0138] The invention also includes any novel intermediates of theformulae (2)-(4), (9)-(15) and (25)disclosed herein.

EXAMPLE

[0139] The present invention is further illustrated in the followingPreparative Examples and Examples, which should not be taken to limitthe scope of the invention.

Preparative Example 1

[0140] Preparation of1-tert-butoxycarbonyl-4-(4-fluoro-n-butyl)piperazine (a compound of theformula (27) wherein n=4, m=0, Z=F)

[0141] A mixture of 1-tert-butoxycarbonylpiperazine (200 mg, 1.07 mmol),1-bromo-4-fluoropropane (170 mg, 1.13 mmol) and sodium bicarbonate (680mg, 8.06 mmol) in anhydrous N,N-dimethylforamide (DMF) (6 mL) wasstirred overnight at 40-50° C. and was cooled to room temperature. Thereaction mixture was filtered through a Celite pad, and the filtrate wasevaporated to dryness under vacuum to afford yellowish oil. The crudeproduct was purified by MPLC on silica gel (1% MeOH in CHCl₃) to affordthe titled compound (182 mg, 66%) as a pale yellow oil.

[0142] IR (neat) 1700 (C═O), 1176 (C—F) cm⁻¹;

[0143]¹H NMR (DMSO-d₆) δ1.46 (s, 9 H, C(CH₃)₃), 1.58-1.78 (m, 4 H,NCH₂CH₂CH₂CH₂F), 2.35-2.42 (m, 6H , 3 NCH₂). 3.43 (dd, J=5.4 Hz, 4.8 Hz,4 H, 2 BocNCH₂), 4.46 (dt, J=47.4 Hz, 6.0 Hz, 2 H CH₂CH₂F); MS (FAB) m/z261 (MH³⁰ ).

Preparative Example 2

[0144] Preparation of 1-(4-fluoro-n-butyl)piperazine trifluoroaceticacid (a compound of the formula (5a) wherein n=4, m=0, Z=F)

[0145] A mixture of 1-tert-butoxycarbonyl-4-(4-fluoro-n-butyl)piperazine(3.50 g, 10.74 mmol) in trifluoroacetic acid (20 mL) was stirred at roomtemperature for 1 h. The reaction mixture was evaporated to drynessunder vacuum and the resulting residue was triturated from Et₂O toafford the titled compound (2.61 g, 87%) as a white solid.

[0146] mp 108.5-109.5° C;

[0147] IR (neat) 1665 (C═O), 1118 (C—F) cm⁻¹;

[0148]¹NMR (CDCl₃/TMS) δ1.58-1.78 (m, 4H, NCH₂CH₂CH₂CH₂F), 3.11 (t,J=6.9 Hz, NCH₂CH₂), 3.30-3.50 (m, 8 H, 2 NCH₂ and 2 BocNCH₂), 4.46 (dt,J=47.7 Hz, 5.4 Hz, 2 H, CH₂CH₂F); MS (FAB) m/z 161 (MH⁺).

Preparative Example 3

[0149] Preparation of1-tert-butoxycarbonyl-4-(2-fluoroethyl)homopiperazine (a compound of theformula (27) wherein n=2, m=1, Z=F)

[0150] A mixture of 1-tert-butoxycarbonylhomopiperazine (800 mg, 3.99mmol), 1-bromo-2-fluoroethane (0.46 mL, 11.98 mmol) and potassiumcarbonate (1.10 g, 7.98 mmol) in anhydrous tetrahydrofuran (20 mL) wasstirred overnight at 70° C. and was cooled to room temperature. Thereaction mixture was filtered through a Celite pad, and the filtrate wasevaporated to dryness under vacuum to afford yellowish oil. The crudeproduct was purified by MPLC on silica gel (3% MeOH in CHCl₃) to affordthe titled compound (653 mg, 67%) as a pale yellow oil.

[0151] IR (neat) 1686 (C═O), 1163 (C—F) cm⁻¹;

[0152]¹H NMR (CDCl₃/TMS) δ1.46 (s, 9 H, C(CH₃)₃), 1.78-1.90 (m, 2 H,NCH₂CH₂CH₂N), 2.68-2.78 (m, 4 H, 2 NCH₂), 2.84 (dt, J=26.7 Hz, 5.1 Hz, 2H, NCH₂CH₂F), 3.40-3.54 (m, 4 H, 2 BocNCH₂), 4.53 (dt, J=47.7 Hz, 5.1Hz, 2 H, NCH₂CH₂F); MS (FAB) m/z 247 (MH⁺).

Preparative Example 4

[0153] Preparation of 1-(2-fluoroethyl)homopiperazine dihydrochloride (acompound of the formula (5a) wherein n=2, m=1, Z=F)

[0154] A mixture of1-tert-butoxycarbonyl-4-(2-fluoroethyl)homopiperazine (550 mg, 2.23mmol) in 10% aqueous hydrochloric acid (2 ml ) and tetrahydrofuran (4mL) was stirred at room temperature for 2 h, and the reaction mixturewas evaporated to dryness under vacuum. Resulting residue was trituratedfrom Et₂O/MeOH to afford the titled compound (475 mg, 97%) as a whitesolid.

[0155] mp 185-186° C.;

[0156] IR (neat) 1069 (C—F) cm⁻¹;

[0157]¹H NMR (DMSO-d₆) δ2.06-2.14 (m, 2H, NCH₂CH₂CH₂N), 3.16-3.76(m, 10H, 5 NCH₂), 4.54(dt, J=47.1 Hz, 5.7 Hz, 2 H, NCH₂CH₂F), 9.57(br s, 1 H,NH⁺), 9.91 (br s, 1 H, NH⁺), 11.70 (br s, 1 H, NH⁺); MS (FAB) m/z 147(MH⁺).

Preparative Example 5

[0158] Preparation of1-tert-butoxycarbonyl-4-(3-fluoro-n-propyl)homopiperazine (a compound ofthe formula (27) wherein n=3, m=1, Z=F)

[0159] The titled compound was prepared as described in PreparativeExample 3 by using 1-bromo-3-fluoropropane in place of1-bromo-2-fluoroethane.

[0160] yield: 76%

[0161] IR (neat) 1700 (C═O), 1174 (C—F) cm⁻¹;

[0162]¹H NMR (CDCl₃/TMS) δ1.46 (s, 9 H, C(CH₃)₃), 1.78-1.91 (m, 4 H,NCH₂CH₂CH₂N and NCH₂CH₂CH₂F), 2.58-2.68 (m, 4 H, 2 NCH₂), 2.61 (t, J=7.2Hz, 2 H, NCH₂CH₂), 3.40-3.52 (m, 4 H, 2 BocNCH₂), 4.50 (dt, J=47.1 Hz,6.0 Hz, 2 H, CH₂CH₂F); MS (FAB) m/z 261 (MH⁺).

Preparative Example 6

[0163] Preparation of 1-(3-fluoro-n-propyl)homopiperazinedihydrochloride (a compound of the formula (5a) wherein n=3, m=1, Z=F)

[0164] The titled compound was prepared as described in PreparativeExample 4 by using1-tert-butoxycarbonyl-4-(3-fluoro-n-propyl)homopiperazine in place of1-tert-butoxycarbonyl-4-(2-fluoroethyl)homopiperazine.

[0165] yield: 88%

[0166] mp 194-195° C. (Et₂O/MeOH);

[0167] IR (neat) 1053 (C—F) cm⁻¹;

[0168]¹H NMR (DMSO-d₆) δ2.06-2.14 (m, 4 H, NCH₂CH₂CH₂N and NCH₂CH₂CH₂F),3.16-3.76 (m, 10 H, 5 NCH₂), 4.54 (dt, J=47.1 Hz, 5.7 Hz, 2 H,NCH₂CH₂F), 9.58 (br s, 1 H, NH⁺), 9.91 (br s, 1 H, NH⁺), 11.70 (br s, 1H, NH⁺); MS (FAB) m/z 161 (MH⁺).

Preparative Example 7

[0169] Preparation of N-(2-cyano-2-n-propylvinyl)-N-methylglycine ethylester (a compound of the formula (20) wherein R¹═CH₃, R²═H,R³═CH₂CH₂CH₃)

[0170] A suspension of 2-cyanopentanal (33.12 g, 0.30 mol),N-methylglycine ethyl ester hydrochloride (62.39 g, 0.45 mol) and sodiumacetate (36.67 g, 0.45 mol) in MeOH (600 mL) was stirred at roomtemperature for 21 h, and the mixture was evaporated to dryness underreduced pressure. Resulting residue was diluted with water (200 mL) andwas extracted with ethyl acetate (200 mL×3). Combined organic layer wasdried (Na₂SO₄), filtered and the filtrate was evaporated to drynessunder reduced pressure to give yellow oil. The crude product waspurified by MPLC on silica gel (1% MeOH in CHCl₃) to afford the titledcompound (47.02 g. 80%) as a pale yellow oil.

[0171] IR (neat) 2180 (CN), 1745 (C═O) cm⁻¹;

[0172]¹H NMR (CDCl₃/TMS) δ0.90 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.30 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.45-1.57 (m, 2 H, CH₂CH₂CH₃), 2.03 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.12 (s, 3 H, NCH₃), 3.97 (s, 2 H, NCH₂CO), 4.24(q, J=6.9 Hz, 2 H, OCH₂CH₃), 6.12 (s, 1 H, CH); MS (FAB) m/z 211 (MH⁺).

Preparative Example 8

[0173] Preparation of N-(2-cyano-2-ethylvinyl)-N-methylglycine methylester (a compound of the Formula (20) wherein R¹═CH₃, R²═H, R³═CH₂CH₃)

[0174] The titled compound was prepared as described in PreparativeExample 7 by using 2-cyanobutyraldehyde and N-methylglycine methyl esterhydrochloride in place of 2-cyanopentanal and N-methylglycine ethylester hydrochloride.

[0175] yield: 62%

[0176] IR (neat) 2184 (CN), 1751 (C═O) cm⁻¹;

[0177]¹H NMR (CDCl₃/TMS) δ1.10 (t, J=7.5 Hz, 3 H, CH₂CH₃), 2.10 (q,J=7.5 Hz, 2 H, CH₂CH₃), 3.12 (s, 3 H, NCH₃), 3.78 (s, 3 H, OCH₃), 3.99(s, 2 H, NCH₂CO), 6.12 (s, 1 H, CH); MS (FAB) m/z 183 (MH⁺).

Preparative Example 9

[0178] Preparation ofN-(2-cyano-2-(3-fluoropropyl)vinyl)-N-methylglycine methyl ester (acompound of the formula (20) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₂F)

[0179] The titled compound was prepared as described in PreparativeExample 7 by using 2-cyano-5-fluoropentanal and N-methylglycine methylester hydrochloride in place of 2-cyanopentanal and N-methylglycineethyl ester hydrochloride.

[0180] yield: 73%

[0181] IR (neat) 2180 (CN), 1741 (C═O) cm⁻¹;

[0182]¹H NMR (CDCl₃/TMS) δ1.78-1.97 (m, 2 H, CH₂CH₂CH₂F), 2.22 (t, J=7.2Hz, 2 H, CH₂CH₂CH₂F), 3.13 (s, 3 H, NCH₃), 3.79 (s, 3 H, OCH₃), 4.01 (s,2 H, NCH₂CO), 4.48 (dt, J=47.1 Hz, 5.7 Hz, 2 H, CH₂CH₂CH₂F), 6.28 (s, 1H, CH); MS (FAB) m/z 215 (MH⁺).

Preparative Example 10

[0183] Preparation ofN-(2-cyano-2-(cyclopropylmethyl)vinyl)-N-methylglycine methyl ester (acompound of the formula (20) wherein R¹═CH₃, R²═H, R³=cyclopropylmethyl)

[0184] The titled compound was prepared as described in PreparativeExample 7 by using 3-cyclopropyl-2-cyanopropionaldehyde andN-methylglycine methyl ester hydrochloride in place of 2-cyanopentanaland N-methylglycine ethyl ester hydrochloride.

[0185] yield: 70%

[0186] IR (neat) 2185 (CN), 1759 (C═O) cm⁻¹;

[0187]¹H NMR (CDCl₃/TMS) δ0.13-0.18 (m, 2 H, c-C₃H₅), 0.46-0.53 (m, 2 H,c-C₃H₅), 0.79-0.93 (m, 1 H, c-C₃H₅), 1.99 (d, J=6.9 Hz, 2 H, CHCH₂),3.13 (s, 3 H, NCH₃), 3.78 (s, 3 H, OCH₃), 4.01 (s, 2 H, NCH₂CO), 6.27(s, 1 H, CH); MS (FAB) m/z 209 (MH⁺).

Preparative Example 11

[0188] Preparation of N-(2-cyano-2-ethylvinyl)-N-ethylglycine methylester (a compound of the formula (20) wherein R¹═CH₂CH₃, R²═H,R³═CH₂CH₃)

[0189] The titled compound was prepared as described in PreparativeExample 7 by using 2-cyanobutyraldehyde and N-ethylglycine methyl esterhydrochloride in place of 2-cyanopentanal and N-methylglycine ethylester hydrochloride.

[0190] yield: 51%

[0191] IR (neat) 2182 (CN), 1752 (C═O) cm⁻¹;

[0192]¹H NMR (CDCl₃/TMS) δ1.10 (t, J=7.5 Hz, 3 H, CH₂CH₃), 1.19 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 2.10 (q, J=7.5 Hz, 2 H, CH₂CH₃), 3.34 (q, J=7.2Hz, 2 H NCH₂CH₃), 3.78 (s, 3 H, OCH₃), 4.09(s, 2 H, NCH₂CO), 6.28 (s, 1H, CH); MS (FAB) m/z 197 (MH⁺).

Preparative Example 12

[0193] Preparation of N-(2-cyano-2-n-propylvinyl)-N-ethylglycine methylester (a compound of the formula (20) wherein R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₃)

[0194] The titled compound was prepared as described in PreparativeExample 7 by using 2-cyanopentanal and N-ethylglycine methyl esterhydrochloride in place of 2-cyanopentanal and N-methylglycine ethylester hydrochloride.

[0195] yield: 61%

[0196] IR (neat) 2179 (CN), 1750 (C═O) cm⁻¹;

[0197]¹NMR (CDCl₃/TMS) δ0.90 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.44-1.57 (m, 2 H, CH₂CH₂CH₃), 2.03 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.34 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 3.79 (s, 3 H,OCH₃), 4.10 (s, 2 H, NCH₂CO), 6.25 (s, 1 H, CH); MS (FAB) m/z 211 (MH⁺).

Preparative Example 13

[0198] Preparation of N-(2-cyano-2-(3-fluoropropyl)vinyl)-N-ethylglycinemethyl ester (a compound of the formula (20) wherein R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₂F)

[0199] The titled compound was prepared as described in PreparativeExample 7 by using 2-cyano-5-fluoropentanal and N-ethylglycine methylester hydrochloride in place of 2-cyanopentanal and N-methylglycineethyl ester hydrochloride.

[0200] yield: 50%

[0201] IR (neat) 2177 (CN), 1 743 (C═O) cm⁻¹;

[0202]¹H NMR (CDCl₃/TMS) δ1.20 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.78-1.96(m, 2 H, CH₂CH₂CH₂F), 2.22 (t, J=7.2 Hz, 2 H, CH₂CH₂CH₂F), 3.35 (q,J=7.2 Hz, 2 H, N CH₂CH₃), 3.79 (s, 3 H, OCH₃), 4.10 (s, 2 H, NCH₂CO),4.48 (dt, J=47.4 Hz, 5.7 Hz, 2 H, CH₂CH₂CH₂F), 6.32 (s, 1 H, CH); MS(FAB) m/z 229 (MH⁺).

Preparative Example 14

[0203] Preparation of N-(2-cyano-2-n-propylvinyl)-N-methylglycine amide(a compound of the formula (19) wherein R¹═CH₃, R²═H, R³═CH₂,CH₂CH₃)

[0204] A suspension of N-(2-cyano-2-n-propylvinyl)-N-methylglycine ethylester (6.00 g, 28.53 mmol) in 29% aqueous ammonia solution (50 mL) wasstirred overnight at room temperature. Resulting precipitates werecollected by filtration, which were washed with cold water and diethylether to afford the titled compound (3.20 g, 62%) as a white solid.Ether layer was separated from the filtrate, and the aqueous layer wasfurther extracted with 3% MeOH in CHCl₃ (50 mL). Combined organic layerwas dried (Na₂SO₄), filtered and the filtrate was evaporated to drynessunder reduced pressure to give a pale yellow solid (1.31 g, 25%).

[0205] mp 106-106.5° C.;

[0206] IR (neat) 3375, 3188 (NH₂), 2179 (CN), 1660, 1636 (C═O) cm⁻¹;

[0207]¹H NMR (CDCl₃/TMS) δ0.91 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.47-1.55(m, 2 H, CH₂CH₂CH₃), 2.05 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.17 (s, 3 H,NCH₃), 3.92 (s, 2 H, NCH₂CO), 5.67 (br s, 1 H, CONH), 5.91 (br s, 1 H,CONH), 6.27 (s, 1 H, CH); MS (FAB) m/z 182 (MH⁺).

Preparative Example 15

[0208] Preparation of N-(2-cyano-2-ethylvinyl)-N-methylglycine amide (acompound of the formula (19) wherein R¹═CH₃, R²═H, R³═CH₂CH₃)

[0209] The titled compound was prepared as described in PreparativeExample 14 by using N-(2-cyano-2-ethylvinyl)-N-methylglycine methylester in place of N-(2-cyano-2-n-propylvinyl)-N-methylglycine ethylester.

[0210] yield: 81%.

[0211] mp 101-102° C. (MeOH/CH₂-Cl₂/ether);

[0212] IR (neat) 3429, 3300 (NH), 2173 (CN), 1694, 1669 (C═O) cm⁻¹;

[0213]¹H NMR (CDCl₃/TMS) δ1.11 (t, J=7.5 Hz, 3 H, CH₂CH₃), 2.11 (q J=7.5Hz, 2 H, CH₂CH₃), 3.16 (s, 3 H, NCH₃), 3.92 (s, 2 H,. NCH₂CO), 5.90 (brs, 1 H, CONH), 5.99 (br s, 1 H, CONH), 6.29 (s, 1 H, CH); MS (FAB) m/z168 (MH⁺).

Preparative Example 16

[0214] Preparation ofN-(2-cyano-2-(3-fluoropropyl)vinyl)-N-methylglycine amide (a compound ofthe formula (19) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₂F)

[0215] The titled compound was prepared as described in PreparativeExample 14 by using N-(2-cyano-2-(3-fluoropropyl)vinyl)-N-methylglycinemethyl ester in place of N-(2-cyano-2-n-propylvinyl)-N-methylglycineethyl ester.

[0216] yield: 70%

[0217] mp 83.5-85° C. (CH₂Cl₂/EtOAc/hexanes);

[0218] IR (neat) 3346, 3173 (NH), 2183 (CN), 1653, 1633 (C═O) cm⁻¹;

[0219]¹H NMR (CDCl₃/TMS) δ1.89-1.99 (m, 2 H, CH₂CH₂CH₂F), 2.23 (t, J=7.8Hz, 2 H, CH₂CH₂CH₂F), 3.17 (s, 3 H, NCH₃), 3.94 (s, 2 H, NCH₂CO), 4.49(dt, J=47.4 Hz, 5.7 Hz, 2 H, CH₂CH₂CH₂F), 5.94 (br s, 2 H, CONH₂), 6.35(s, 1 H, CH); MS (FAB) m,/z 180 (MH⁺—H₂O).

Preparative Example 17

[0220] Preparation ofN-(2-cyano-2-(cyclopropylmethyl)vinyl)-N-methylglycine amide (a compoundof the formula (19) wherein R¹═CH₃, R²═H, R³=cyclopropylmethyl)

[0221] The titled compound was prepared as described in PreparativeExample 14 by usingN-(2-cyano-2-(cyclopropylmethyl)vinyl)-N-methylglycine methyl ester inplace of N-(2-cyano-2-n-propylvinyl)-N-methylglycine ethyl ester.

[0222] yield: 85%

[0223] mp 100.5-102° C. (CH₂Cl/ether);

[0224] IR (neat) 3352, 3173 (NH), 2179 (CN), 1656, 1639 (C═O) cm⁻¹;

[0225]¹H NMR (CDCl₃/TMS) δ0.13-0.19 (m, 2 H, c-C₃H₅), 0.48-0.56 (m, 2 H,c-C₃H₅), 0.79-0.93 (m, 1 H, c-C₃H₅),2.00 (d, J=6.9 Hz, 2 H, CHCH₂), 3.18(s, 3 H, NCH₃), 3.93 (s, 2 H, NCH₂CO), 5.81 (br s, 1 H, CONH), 5.98 (brs, 1 H, CONH), 6.32 (s, 1 H, CH); MS (FAB) m/z 194 (MH⁺).

Preparative Example 18

[0226] Preparation of N-(2-cyano-2-ethylvinyl)-N-ethylglycine amide (acompound of the formula (19) wherein R¹═CH₂CH₃CH₃, R²═H, R³═CH₂CH₃)

[0227] The titled compound was prepared as described in PreparativeExample 14 by using N-(2-cyano-2-ethylvinyl)-N-ethylglycine methyl esterin place of N-(2-cyano-2-n-propylvinyl)-N-methylglycine ethyl ester.

[0228] yield: 77%

[0229] mp 89-90° C. (ether/hexanes);

[0230] IR (neat) 3386, 3186 (NH), 2178 (CN), 1664, 1634 (C═O) cm⁻¹;

[0231]¹H NMR (CDCl₃/TMS) δ1.11 (t, J=7.5 Hz, 3 H, CH₂CH₃), 1.22 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 2.11 (q, J=7.5 Hz, 2 H, CH₂CH₃), 3.41 (q, J=7.2Hz, 2 H, N CH₂CH₃),3.98 (s, 2 H, NCH₂CO), 5.77 (br s, 1 H, CONH), 6.01(br s, 1 H, CONH), 6.30 (s, 1 H, CH); MS (FAB) m/z 182 (MH⁺).

Preparative Example 19

[0232] Preparation of N-(2-cyano-2-n-propylvinyl)-N-ethylglycine amide(a compound of the formula (19) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₃)

[0233] The titled compound was prepared as described in PreparativeExample 14 by using N-(2-cyano-2-n-propylvinyl)-N-ethylglycine methylester in place of N-(2-cyano-2-n-propylvinyl)-N-methylglycine ethylester.

[0234] yield: 90%

[0235] mp 71.5-73° C.(ether/hexanes);

[0236] IR (neat) 3392, 3188 (NH₂), 2174 (CN), 1675, 1633 (C═O) cm⁻¹;

[0237]¹H NMR (CDCl₃/TMS) δ0.91 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.22 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.46-1.58 (m, 2 H, CH₂CH₂CH₃), 2.05 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.42 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 3.99 (s, 2 H,NCH₂CO), 5.64 (br s, 1 H, CONH), 5.97 (br s, 1 H, CONH), 6.28 (s, 1 H,CH); MS (FAB) m/z 196 (MH⁺).

Preparative Example 20

[0238] Preparation of N-(2-cyano-2-(3-fluoropropyl)vinyl)-N-ethylglycineamide (a compound of the formula (19) wherein R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₂F)

[0239] The titled compound was prepared as described in PreparativeExample 14 by using N-(2-cyano-2-(3-fluoropropyl)vinyl)-N-ethylglycinemethyl ester in place of N-(2-cyano-2-n-propylvinyl)-N-methylglycineethyl ester.

[0240] yield: 86%

[0241] mp 70-71° C. (ether/hexanes);

[0242] IR (neat) 3324, 3198 (NH), 2177 (CN), 1684, 1617 (C═O) cm⁻¹;

[0243]¹H NMR (CDCl₃/TMS) δ1.23 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.79-1.97(m, 2 H, CH₂CH₂CH₂F), 2.24 (t, J=7.2 Hz, 2 H, CH₂CH₂CH₂F), 3.41 (q,J=7.2 Hz, 2 H, NCH₂CH₃), 4.01 (s, 2 H, NCH₂CO), 4.48 (dt, J=47.1 Hz, 5.7Hz, 2 H, CH₂CH₂CH₂F), 5.93 (br s, 2 H, CONH₂), 6.35 (s, 1 H, CH); MS(FAB) m/z 214 (MH⁺).

Preparative Example 21

[0244] Preparation of 4-amino-1-methyl-3-n-propylpyrrole-5-carboxamide(a compound of the formula (15) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH³)

[0245] A solution of N-(2-cyano-2-n-propylvinyl)-N-methylglycine amide(8.26 g, 45.57 mmol) in freshly prepared NaOEt in EtOH (0.5 M, 190 mL,95.71 mmol) was heated at 60° C. for 1.5 h, cooled to room temperatureand then the mixture was quenched with acetic acid (5.4 mL). Resultingmixture was diluted with water (50 mL) and was extracted with CH₂CH₂(100 mL×3). Combined organic layer was dried (Na₂SO₄), filtered and thefiltrate was evaporated to dryness under reduced pressure. The crudeproduct was dissolved in a minimum amount of CH₂Cl₂, and then solidifiedby adding diethyl ether and hexanes to afford the titled compound (7.64g, 92%) as a pale violet solid.

[0246] mp 123-124° C.;

[0247] IR (neat) 3353, 3181 (NH₂), 1647 (C═O) cm⁻¹;

[0248]¹H NMR (CDCl₃/TMS) δ0.96 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃),1.49-1.61(m, 2 H, CH₂CH₂CH₃), 2.31 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.17(br s, 2 H, NH₂), 3.83 (s, 3 H, NCH₃), 6.34 (br s, 2 H, CONH₂), 6.37(s,1 H, H-2); MS (FAB) m/z 182 (MH⁺).

Preparative Example 22

[0249] Preparation of 4-amino-3-ethyl-1-methylpyrrole-5-carboxamide (acompound of the formula (15) wherein R¹═CH₃, R²═H, R³═CH₂CH₃)

[0250] The titled compound was prepared as described in PreparativeExample 21 by using N-(2-cyano-2-ethylvinyl)-N-methylglycine amide inplace of N-(2-cyano-2-n-propylvinyl)-N-methylglycine amide.

[0251] yield: 79%

[0252] mp 113.5-115° C. (MeOH/EtOAc/hexanes);

[0253] IR (neat) 3373, 3180 (NH), 1653, 1611 (C═O) cm⁻¹;

[0254]¹H NMR (CDCl₃/TMS) δ1.18 (t, J=7.5 Hz, 3 H, CH₂CH₃), 2.36 (q,J=7.5 Hz, 2 H, CH₂CH₃), 3.18 (br s, 2 H, NH₂), 3.83 (s, 3 H, NCH₃), 6.35(br s, 2 H, CONH₂), 6.38 (s, 1 H, H-2; MS (FAB) m/z 168 (MH⁺).

Preparative Example 23

[0255] Preparation of4-amino-3-(3-fluoropropyl)-1-methylpyrrole-5-carboxamide (a compound ofthe formula (15) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₂F)

[0256] The titled compound was prepared as described in PreparativeExample 21 by using N-(2-cyano-2-(3-fluoropropyl)vinyl)-N-methylglycineamide in place of N-(2-cyano-2-n-propylvinyl)-N-methylglycine amide.

[0257] yield: 66%

[0258] mp 124-125.5° C. (CH₂Cl₂/EtOAc/ether);

[0259] IR (neat) 3347, 3175 (NH), 1642, 1601 (C═O) cm⁻¹;

[0260]¹H NMR (CDCl₃/TMS) δ1.91-2.00 (m, 2 H, CH₂CH₂CH₂F), 2.50 (t, J=7.5Hz, 2 H, CH₂CH₂CH₂F), 3.16 (br s, 2 H, NH₂), 3.84 (s, 3 H, NCH₃), 4.47(dt, J=47.1 Hz, 5.7 Hz, 2 H, CH₂CH₂CH₂F), 6.34 (br s, 2 H, CONH₂), 6.40(s, 1 H, H-2); MS (FAB) m/z 200 (MH⁺).

Preparative Example 24

[0261] Preparation of4-amino-3-cyclopropylmethyl-1-methylpyrrole-5-carboxamide (a compound ofthe formula (15) wherein R¹═CH₃, R²═H, R³=cyclopropylmethyl)

[0262] The titled compound was prepared as described in PreparativeExample 21 by usingN-(2-cyano-2-(cyclopropylmethyl)vinyl)-N-methylglycine amide in place ofN-(2-cyano-2-n-propylvinyl)-N-methylglycine amide.

[0263] yield: 73%,

[0264] mp 135-137° C. (CH₂Cl₂/ether/hexanes);

[0265] IR (neat) 3348, 3150 (NH), 1655 (C═O) cm⁻¹;

[0266]¹H NMR (CDCl₃/TMS) δ0.11-0.16 (m, 2 H, c-C₃H₅), 0.48-0.54 (m, 2 H,c-C₃H₅), 0.83-0.97 (m, 1 H, c-C₃H₅), 2.30 (d, J=6.3 Hz, 2 H, CHCH₂),3.20 (br s, 2 H, NH₂) 3.84 (s, 3 H, NCH₃), 6.34 (br s, 2 H, CONH₂), 6.47(s, 1 H, H-20; MS (FAB) m/z 193 (M⁺).

Preparative Example 25

[0267] Preparation of 4-amino-1-ethyl-3-ethylpyrrole-5-carboxamide (acompound of the formula (15) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₃)

[0268] The titled compound was prepared as described in PreparativeExample 21 by using N-(2-cyano-2-ethylvinyl)-N-ethylglycine amide inplace of N-(2-cyano-2-n-propylvinyl)-N-methylglycine amide.

[0269] yield: 89%

[0270] mp 94° C. dec (CH₂Cl₂/ether/hexanes);

[0271] IR (neat) 3367, 3178 (NH), 1608 (C═O) cm⁻¹;

[0272]¹H NMR (CDCl₃/TMS) δ1.19 (t, J=7.5 Hz, 3 H, CH₂CH₃), 1.34 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 2.37 (q, J=7.5 Hz, 2 H, CH₂CH₃), 3.11 (br s, 2H, NH₂), 4.28 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 6.38 (br s, 2 H, CONH₂), 6.47(s, 1 H, H-2); MS (FAB) m/z 182 (MH⁺).

Preparative Example 26

[0273] Preparation of 4-amino-1-ethyl-3-n-propylpyrrole-5-carboxamide (acompound of the formula (15) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₃)

[0274] The titled compound was prepared as described in PreparativeExample 21 by using N-(2-cyano-2-n-propylvinyl)-N-ethylglycine amide inplace of N-(2-cyano-2-propylvinyl )-N-methylglycine amide.

[0275] yield: 89%

[0276] mp 108.5-110° C. (ether/hexanes);

[0277] IR (neat) 3366, 3183 (NH), 1628 (C═O) cm⁻¹;

[0278]¹H NMR (CDCl₃/TMS) δ0.96 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.33 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.49-1.62 (m, 2 H, CH₂CH₂CH₃), 2.32 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.10 (br s, 2 H, NH₂), 4.28 (q, J=7.2 Hz, 2 H,NCH₂CH₃), 6.38 (br s, 2 H, CONH₂), 6.46 (s, 1 H, H-2): MS (FAB) m/z 196(MH⁺).

Preparative Example 27

[0279] Preparation of4-amino-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide (a compound ofthe formula (15) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₂F)

[0280] The titled compound was prepared as described in PreparativeExample 21 by using N-(2-cyano-2-(3-fluoropropyl)vinyl)-N-ethylglycineamide in place of N-(2-cyano-2-n-propylvinyl)-N-methylglycine amide.

[0281] yield: 90%

[0282] mp 94.5-96° C. (CH₂Cl₂/ether);

[0283] IR (neat) 3346, 3179 (NH), 1629 (C═O) cm⁻¹;

[0284]¹H NMR (CDCl₃/TMS) δ1.34 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.82-2.00(m, 2 H, CH₂CH₂CH₂F), 2.51 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₂F), 3.14 (br s, 2H, NH₂), 4.28 (q. J=7.2 Hz, 2 H, NCH₂CH₃), 4.47 (dt, J=47.4 Hz, 5.7 Hz,2 H, CH₂CH₂CH₂F), 6.38 (br s, 2 H, CONH₂), 6.48 (s, 1 H, H-2); MS (FAB)m/z 214 (MH⁺).

Preparative Example 28

[0285] Preparation of4-(2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide (acompound of the formula (12) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0286] To a cooled mixture of4-amino-1-methyl-3-n-propylpyrrole-5-carboxamide (3.00 g, 16.55 mmol),DMAP (101 mg, 0.83 mmol) and triethylamine (4.6 mL, 33.00 mmol) inCH₂Cl₂ (50 mL) in an ice bath was added dropwise 2-ethoxybenzoylchloride in CH₂Cl₂ (30 mL) over a period of 10 minutes, and the reactionmixture was stirred in an ice bath for 1 h. The reaction was quenchedwith 1 N HCl solution (100 mL), and was extracted with 3% MeOH in CHCl₃(3×100 mL). The combined organic layer was washed with saturated aqueousNaHCO₃ (50 mL), dried (MgSO₄), and filtered. The filtrate was evaporatedto dryness in vacuo to afford an off-white solid, and the crude productwas purified by MPLC on silica gel (2% MeOH in CHCl₃) to afford thetitled compound (5.01 g, 92%) as a white solid. Analytically purecompound was obtained by crystallization from ethyl acetate/hexanes.

[0287] mp 166-167° C.;

[0288] IR (neat) 3334, 3149 (NH), 1668, 1641 (C═O) cm⁻¹;

[0289]¹H NMR (CDCl₃/TMS) δ0.92 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.47-1.59(m, 2 H, CH₂CH₂CH₃), 1.52 (t, J=6.6 Hz, 3 H, OCH₂CH₃), 2.34 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.85 (s, 3 H, NCH₃), 4.29 (q, J=6.6 Hz, 2 H,OCH₂CH₃), 6.52 (s, 1 H, H-2), 7.04 (d, J=8.4 Hz, 1 H, H-3′), 7.09-7.15(m, 1 H, H-5′), 7.51 (ddd, J=8.4 Hz, 7.2 Hz, 1.8 Hz, 1 H, H-4′), 8.29(dd, J=8.1 Hz, 1.8 Hz, 1 H, H-6′), 9.37 (br s, 1 H, NH): MS (FAB) m/z330 (MH⁺).

Preparative Example 29

[0290] Preparation of1-methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamide (acompound of the formula (12) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0291] The titled compound was prepared as described in PreparativeExample 28 by using 2-n-propoxybenzoyl chloride in place of2-ethoxybenzoyl chloride.

[0292] yield: 91%

[0293] mp 136-137° C. (CHCl₃/Et₂O/hexanes);

[0294] IR (neat) 3338, 3159 (NH), 1646 (C═O) cm⁻¹;

[0295]¹H NMR (CDCl₃/TMS) δ0.91 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.06 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.47-1.57 (m, 2 H, CH₂CH₂CH₃), 1.85-1.95 (m,2 H, OCH₂CH₂CH₃), 2.33 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.85 (s, 3 H,NCH₃), 4.18 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6.52 (s, 1 H, H-2), 7.04 (d,J=8.4 Hz, 1 H, H-3′), 7.12 (td, J=8.1 Hz, 0.9 Hz, 1 H, H-5′), 7.48-7.54(m, 1 H, H-4′), 8.29 (dd, J=8.1 Hz, 2.1 Hz, 1 H, H-6′), 9.36 (br s, 1 H,NH); MS (FAB) m/z 344 (MH⁺).

Preparative Example 30

[0296] Preparation of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₃, R²═H, R³═CH₂CH₃,R⁴═CH₂CH₃, R¹⁶=4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)

[0297] To a mixture of 4-amino-3-ethyl-1-methylpyrrole-5-carboxamide(125 mg, 0.74 mmol),2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzoicacid (279 mg, 0.74 mmol), HOBT (151 mg, 1.12 mmol), and DMAP (18 mg,0.15 mmol) in anhydrous pyridine (5 mL) at room temperature undernitrogen atmosphere was slowly added EDC (214 mg, 1.12 mmol) over aperiod of 5 minutes, and the reaction mixture was stirred for 2 h.Pyridine was removed under vacuum and the resulting residue as dilutedwith brine (100 ml). Extraction with 5% MeOH in CHCl₃ (2×100 mL) wasperformed and the combined organic layer was dried (MgSO₄), andfiltered. The filtrate as evaporated to dryness in vacuo to afford abrown solid, and the crude product was purified by MPLC on silica gel(gradient elution: 2% MeOH in CHCl₃ followed by 3% MeOH in CHCl₃) toafford the titled compound (310 mg, 80%) as a yellowish solid.Analytically pure compound was obtained by crystallization fromCH₂Cl₂/MeOH/hexanes.

[0298] mp 182.5-183° C.;

[0299] IR (neat) 3353 (NH), 1648 (C═O), 1170 (SO₂) cm⁻¹:

[0300]¹H NMR (CDCl₃/TMS) δ1.16 (t, J=7.5 Hz, 3 H, CH₂CH₃), 1.58 (t,J=7.2 Hz, 3 H, OCH₂CH₃), 1.72-1.90 (m, 2 H, CH₂CH₂F), 2.39 (q, J=7.5 Hz,2 H, CH₂CH₃), 2.47 (t, J=7.2 Hz, 2 H, NCH₂CH₂), 2.53 (dd, J=4.8 Hz, 4.5Hz, 4 H, 2 NCH₂), 3.05 (dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 3.85 (s,3 H, NCH₃), 4.37 (q, J=7.2 Hz, 2 H, OCH₂CH₃), 4.42 (dt, J=47.4 Hz, 6.0Hz, 2 H, CH₂CH₂F), 6.54 (s, 1 H, H-2), 7.16 (d, J=8.7 Hz, 1 H, H-3′),7.89 (dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.64 (d, J=2.7 Hz, 1 H, H-6′),9.19 (br s, 1 H, NH); MS (FAB) m/z 524 (MH⁺).

Preparative Example 31

[0301] Preparation of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-(3-fluoropropyl)-1-methylpyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₂F,R⁴═CH₂CH₃, R¹⁶=4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)

[0302] The titled compound was prepared as described in PreparativeExample 30 by using(4-amino-3-(3-fluoropropyl)-1-methylpyrrole-5-carboxamide in place of4-amino-3-ethyl-1-methylpyrrole-5-carboxamide.

[0303] yield: 86%

[0304] mp 169-171° C. (CH₂Cl₂/hexanes);

[0305] IR (neat) 3352 (NH), 1647 (C═O), 1170 (SO₂) cm⁻¹:

[0306]¹H NMR (CDCl₃/TMS) δ1.57 (t, J=7.2 Hz, 3 H, OCH₂CH₃), 1.72-1.98(m, 4 H, 2 CH₂CH₂F), 2.47 (t, J=7.5 Hz, 2 H, NCH₂CH₂), 2.46-2.60 (m, 6H, CH₂CH₂CH₂F) and 2 NCH₂), 3.06 (br s, 4 H, 2 SO₂NCH₂) 3.86 (s, 3 H,NCH₃); 4.37 (q, J=7.2 H, 2 H, OCH₂/CH₃), 4.42 (dt, J=47.4 Hz, 5.1 Hz, 4H, 2 CH₂CH₂F), 6.56 (s, 1 H, H-2), 7.16 (d, J=9.0 Hz, 1 H, H-3′), 7.89(dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′) 8.62 (d, J=2.4 Hz, 1 H, H-6′), 9.20(br s, 1 H, NH); MS (FAB) m/z 556 (MH⁺).

Preparative Example 32

[0307] Preparation of3-cyclopropylmethyl-4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1ylsulfonyl)benzamido-1-methylpyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₃, R²═H,R³=cyclopropylmethyl, R⁴═CH₂CH₃,R¹⁶=4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)

[0308] The titled compound was prepared as described in PreparativeExample 30 by using4-amino-3-cyclopropylmethyl-1-methylpyrrole-5-carboxamide in place of4-amino-3-ethyl-1-methylpyrrole-5-carboxamide.

[0309] yield: 91%

[0310] mp 198-199° C. (CH₂Cl₂/ether);

[0311] IR (neat) 3359, 3288 (NH), 1642 (C═O), 1170 (SO₂) cm⁻¹;

[0312]¹H NMR (CDCl₃/TMS) δ0.09-0.14 (m, 2 H, c-C₃H₅), 0.45-0.51 (m, 2 H,c-C₃H₅), 0.83-0.97 (m, 1 H, c-C₃ ₅), 1.57 (t, J=6.9 Hz, 3 H, OCH₂CH₃),1.73-1.90 (m, 2 H, CH₂CH₂F), 2.29 (d, J=6.9 Hz, 2 H, CHCH₂), 2.47 (t,J=7.5 Hz, 2 H, NCH₂CH₂), 2.54 (dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 NCH₂), 3.07(dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 3.87 (s, 3 H, NCH₃), 4.37 (q,J=6.9 Hz, 2 H, OCH₂CH₃), 4.44 (dt, J=47.4 Hz, 6.0 Hz, 2 H, CH₂CH₂F),6.66 (s, 1 H, H-2), 7.16 (d, J=8.7 Hz, 1H, H-3′), 7.90 (dd, J=8.7 Hz,2.4 Hz, 1 H, H-4′), 8.64 (d, J=2.4 Hz, 1 H, H-6′), 9.18 (br s, 1 H, NH);MS (FAB) m/z 550 (MH⁺).

Preparative Example 33

[0313] Preparation of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-1ethyl-3-ethylpyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₃,R⁴═CH₂CH₃R¹⁶=4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)

[0314] The titled compound was prepared as described in PreparativeExample 30 by using 4-amino-1-ethyl-3-ethylpyrrole-5-carboxamide and2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)benzoic acid in place of4-amino-3-ethyl-1-methylpyrrole-5-carboxamide and2-ethoxy-5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)benzoic acid

[0315] yield: 68%

[0316] mp 203-204° C. (CH₂Cl₂/ether);

[0317] IR (neat) 3346 (NH), 1646 (C═O), 1173 (SO₂) cm⁻¹;

[0318]¹H NMR (CDCl₃/TMS) δ1.17 (t, J=7.5 Hz, 3 H, CH₂CH₃), 1.41 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.58 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.72-1.89 (m,2 H, CH₂CH₂F), 2.39 (q, J=7.5 Hz, 2 H, CH₂CH₃), 2.47 (t, J=7.2 Hz, 2 H,NCH₂CH₂CH₂F), 2.53 (dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 NCH₂), 3.06 (br dd,J=4.8 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 4.27 (q, J=7.2 Hz, 2 H, NCH₂CH₃),4.37 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.44 (dt, J=47.1 Hz, 6.0 Hz, 2 H,CH₂CH₂F), 6.61 (s, 1 H, H-2), 7.15 (d, J=8.7 Hz, 1 H, H-3′), 7.89 (dd,J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.64 (d, J=2.7 Hz, 1 H, H-6′), 9.18 (br s,1 H, NH); MS (FAB) m/z 538 (MH⁺).

Preparative Example 34

[0319] Preparation of4-(2-ethoxy-5-(4-ethylpiperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3n-propylpyrrole-5-carboxamide (a compound of the formula (25)wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃,R¹⁶=4-ethylpiperazinylpiperazin-1-ylsulfonyl)

[0320] The titled compound was prepared as described in PreparativeExample 30 by using 4-amino-1-ethyl-3-propylpyrrole-5-carboxamide and2-ethoxy-5-(4-ethylpiperazinylpiperazin-1-N-ylsulfonyl)benzoic acid inplace of 4-amino-3-ethyl-1-methylpyrrole -5-carboxamide and2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzoicacid

[0321] yield 87%

[0322] mp 157.5-158.5° C. (CH₂Cl₂/EtOAc/ether/hexanes);

[0323] IR (neat) 3366 (NH), 1644 (═O), 1172 (SO₂cm⁻¹;

[0324]¹H NMR (CDCl₃/TMS) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.03 (t,J=7.2 Hz, 3 H, CH₂NCH₂CH₃), 1.41 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.57 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.48-1.61 (m, 2 H, CH₂CH₂CH₃), 2.34 (t,J=7.5Hz, 2 H, CH₂CH₂CH₃), 2.41 (q, J=7.2 Hz, 2 H, CH₂NCH₂CH₃), 2.53 (dd,J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 3.07 (br dd, J=5.1 Hz, 4.8 Hz, 4 H, 2SO₂NCH₂), 4.27 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 4.37 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.60 (s, 1 H; H-2), 7.15 (d, J=8.7 Hz, 1 H, H-3′), 7.90 (dd,J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.66 (d, J=2.7 Hz, 1 H, H-6′), 9.18 (br s,1 H, NH); MS,(FAB) m/z 520 (MH⁺).

Preparative Example 35

[0325] Preparation of4-(2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-n-propylpyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₂CH₃, R²H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃, R¹⁶=4-isopropylpiperazinylpiperazin-1-ylsulfonyl)

[0326] The titled compound was prepared as described in PreparativeExample 30 by using 4-amino-1-ethyl-3-n-propylpyrrole-5-carboxamide and2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1-ylsulfonyl)benzoic acid inplace of 4-amino-3-ethyl-1-methylpyrrole-5-carboxamide and2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzoicacid

[0327] yield: 64%

[0328] mp 174-175° C. (CH₂Cl₂/EtOAc/ether);

[0329] IR (neat) 3313 (NH), 1646 (C═O), 1169 (SO₂) cm⁻¹;

[0330]¹H NMR (CDCl₃/TMS) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.00 (t,J=6.6 Hz, 6 H, CH₂(CH₃)₂), 1.41 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.48-1.61(m, 2 H, CH₂CH₂CH₃), 1.57 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 2.34 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 2.60 ((dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 NCH₂) 2.63-2.71(m, 1 H, CH(CH₃)₁, 3.05 (br dd, J=4.8 Hz, 4.5 Hz, 4 H, SO₂NCH₂) 4.26 (q,J=7.2 Hz, 2 H, NCH₂CH₃), 4.36 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 6.60 (s, 1 H,H-2), 7.14 (d, J=8.7 Hz, 1 H, H-3′), 7.89 (dd, J=8.7 Hz, 2.4 Hz, 1 H,H-4′), 8.65 (d, J=2.4 Hz, 1 H, H-6′), 9.17 (br s, 1 H, NH); MS (FAB) m/z534 (MH⁺).

Preparative Example 36

[0331] Preparation of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-n-propylpyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃, R¹⁶=4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)

[0332] The titled compound was prepared as described in PreparativeExample 30 by using 4-amino-1-ethyl-3-n-propylpyrrole-5-carboxamide inplace of 4-amino-3-ethyl-1-methylpyrrole-5-carboxamide.

[0333] yield: 91%

[0334] mp 176-176.5° C. (CH₂Cl₂/ether);

[0335] IR (neat) 3358 (NH), 1649 (C═O), 1172 (SO₂) cm⁻¹;

[0336]¹H NMR (CDCl₃/TMS) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.41 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.48-1.61 (m, 2 H, CH₂CH₂CH₃), 1.58 (t, J=6.9Hz, 3 H, OCH₂CH₃), 1.72-1.89 (m, 2 H, NCH₂CH₂CH₂F), 2.34 (q, J=7.5 Hz, 2H, CH₂CH₂CH₃), 2.47 (t, J=7.2 Hz, 2 H, NCH₂CH₂CH₂F), 2.53 (dd, J=4.8 Hz,4.5 Hz, 4 H, 2 NCH₂), 3.07 (br dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂),4.27 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 4.37 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.44(dt, J=47.1 Hz, 6.0 Hz, 2 H, CH₂CH₂F), 6.60 (s, 1 H, H-2), 7.16 (d,J=8.7 Hz, 1 H, H-3′), 7.89 (dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.65 (d,J=2.7 Hz, 1 H, H-6′), 9.17 (br s, 1 H, NH); MS (FAB) m/z 552 (MH⁺).

Preparative Example 37

[0337] Preparation of4-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-n-propylpyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃, R¹⁶=4-(2-hydroxyethylpiperazinylpiperazin-1-ylsulfonyl).

[0338] The titled compound was prepared as described in PreparativeExample 30 by using 4-amino-1-ethyl-3-n-propylpyrrole-5-carboxamide and2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)benzoicacid in place of 4-amino-3-ethyl-1-methylpyrrole-5-carboxamide and2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzoicacid

[0339] yield: 92%

[0340] mp 184-185° C. (CH₂Cl₂/ether);

[0341] IR (neat) 3349 (NH), 1650 (C═O), 1170 (SO₂) cm⁻¹;

[0342]¹H NMR (CDCl₃/TMS) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.41 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.49-1.61 (m, 2 H, CH₂CH₂CH₃), 1.58 (t, J=6.9Hz, 3 H, OCH₂CH₃), 2.34 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.55 (t, J=5.4Hz, 2 H, NCH₂CH₂OH), 2.61 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 3.09 (brdd, J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 3.59 (t, J=5.4 Hz, 2 H,NCH₂CH₂OH), 4.27 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 4.39 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.61 (s, 1 H, H-2), 7.18 (d, J=8.7 Hz, 1 H, H-3′), 7.91 (dd,J=8.7 Hz, 2.7 Hz, 1 H H-4′), 8.66 (d, J=2.4 Hz, 1 H, H-6′), 9.18 (br s,1 H, NH); MS (FAB) m/z 536 (MH⁺).

Preparative Example 38

[0343] Preparation of4-(2-ethoxy-5-(4-ethylpiperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂ CH₃F,R⁴═CH₂CH₃, R¹⁶=4-ethylpiperazinylpiperazin-1-ylsulfonyl)

[0344] The titled compound was prepared as described in PreparativeExample 30 by using 4-amino-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide and2-ethoxy-5(4-ethylpiperazinylpiperazin-1-ylsulfonyl)benzoic acid inplace of 4-amino-3-ethyl-1-methylpyrrole-5carboxamide and2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzoicacid

[0345] yield: 87%

[0346] mp 151-152° C. (CH₂Cl₂/EtOAc/ether/hexanes);

[0347] IR (neat) 3354 (NH), 1664 (C═O), 1170 (SO₂) cm⁻¹:

[0348]¹H NMR (CDCl₃/TMS) δ1.03 (t, J=7.2 Hz, 3 H, CH₂NCH₂CH₃), 1.41 (t,J=7.2 Hz, 3 H, CHNCH₂CH₃), 1.57 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.81-1.98(m, 2 H, CH₂CH₂CH₂F), 2.41 (q, J=7.2 Hz, 2 H, CH₂NCH₂CH₃), 2.49-2.54 (m,6 H, CH₂CH₂CH₂F and 2 NCH₂), 3.07 (m, 4 H, 2 SO₂NCH₂), 4.27 (q, J=7.2Hz, 2 H, CHNCH₂CH₃), 4.36 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.44(dt, J=47.4Hz, 5.7 Hz, 2H, CH₂CH₂CH₂F), 6.63 (s, 1 H, H-2), 7.15 (d, J=8.7 Hz, 1 H,H-3′), 7.90 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.64 (d, J=2.4 Hz, 1 H,H-6′), 9.19 (br s, 1 H, NH); MS (FAB) m/z 538 (MH⁺).

Preparative Example 39

[0349] Preparation of4-(5-(4-ethylpiperazinylpiperazin-1-ylsulfonyl)-2-n-propoxybenzamido)-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₃F,R⁴═CH₂CH₂CH₃, R¹⁶ 32 4-ethylpiperazinylpiperazin-1-ylsulfonyl)

[0350] The titled compound was prepared as described in PreparativeExample 30 by using 4-amino-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide and5-(4-ethylpiperazinylpiperazin-1-ylsulfonyl)-2-n-propoxybenzoic acid inplace of 4-amino-3-ethyl-1-methylpyrrole-5-carboxamide and2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzoicacid

[0351] yield: 77%

[0352] mp 155-156° C. (EtOAc/ether/hexanes);

[0353] IR (neat) 3361 (NH), 1641 (C═O), 1163 (SO₂) cm⁻¹;

[0354]¹H NMR (CDCl₃/TMS) δ1.03 (t, J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.08 (t,J=7.2 Hz, 3 h, CH₂NCH₂CH₃), 1.41 (t, J=7.2 Hz, 3 H, CHNCH₂CH₃),1.80-2.01 (m, 4 H, CH₂CH₂CH₂F and OCH₂CH₂CH₃), 2.41 (q, J=7.2 Hz, 2 H,CH₂NCH₂CH₃), 2.48-2.55 (m, 6 H, CH₂CH₂CH₂F and 2 NCH₂), 3.07 (br dd,J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 4.25 (t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃),4.28 (q, J=7.2 Hz, 2 H. CHNCH₂CH₃), 4.43 (dt, J=47.4 Hz, 5.7 Hz, 2 H,CH₂CH₂CH₂F), 6.63 (s, 1 H, H-2), 7.15 (d, J=8.7 Hz, 1 H, H-3′), 7.89(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.63 (d, J=2.4 Hz, 1 H, H-6′), 9.18(br s, 1 H, NH); MS (FAB) m/z 534 (MH⁺).

Preparative Example 40

[0355] Preparation of4-(2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₂F,R⁴═CH₂CH₃, R¹⁶=4-isopropylpiperazinylpiperazin-1-ylsulfonyl)

[0356] The titled compound was prepared as described in PreparativeExample 30 by using4-amino-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide and2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1ylsulfonyl)benzoic acid inplace of 4-amino-3-ethyl-1-methylpyrrole-5-carboxamide and2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzoicacid

[0357] yield: 80%

[0358] mp 168-169° C. (EtOAc/ether/hexanes);

[0359] IR (neat) 3353 (NH), 1648 (C═O), 1177 (SO₂) cm⁻¹;

[0360]¹H NMR (CDCl₃/TMS) δ1.00 (d, J=6.6 Hz, 6 H, CH(CH₃)₂), 1.41 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.57 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.81-1.99 (m,2 H, CH₂CH₂CH₂F), 2.52 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₂F), 2.60-(dd, J=5.1Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.63-2.71 (m, 1 H, CH(CH₃)₂), 3.05 (br dd,J=5.1 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 4.27 (q, J=7.2 Hz, 2 H, NCH₂CH₃),4.36 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.44(dt, J=47.4 Hz, 5.7 Hz, 2 H,CH₂CH₂CH₂F), 6.63 (s, 1 H, H-2), 7.14 (d, J=8.7 Hz, 1 H, H-3′). 7.89(dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.63 (d, J=2.7 Hz, 1 H, H-6′), 9.19(br s, 1 h, NH); MS (FAB) m/z 552 (MH⁺).

Preparative Example 41

[0361] Preparation of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1ylsulfonyl)benzamido)-1ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₂F,R⁴═CH₂CH₃, R¹⁶=4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)

[0362] The titled compound was prepared as described in PreparativeExample 30 by using4-amino-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide in place of4-amino-3-ethyl-1-methylpyrrole-5-carboxamide

[0363] yield: 85%

[0364] mp 165-166° C. (EtOAc/ether);

[0365] IR (neat) 3354 (NH), 1648 (C═O), 1172 (SO₂) cm⁻¹;

[0366]¹H NMR (CDCl₃/TMS) δ1.42 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.57 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.72-1.98 (m, 4 H, CH₂CH₂CH₂F and NCH₂CH₂CH₂F),2.45-2.55(m, 8H, 2 NCH₂, CH₂CH₂CH₂F and NCH₂CH₂CH₂F), 3.07 (m, 4 H, 2SO₂NCH₂), 4.27 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 4.37 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 4.44(dt, J=47.4 Hz, 6.0 Hz, 4 H, CH₂CH₂CH₂F and NCH₂CH₂CH₂F),6.63 (s, 1 H, H-2), 7.16 (d, J=8.7 Hz, 1 H, H-3′), 7.89 (dd, J=8.7 Hz,2.4 Hz, 1 H, H-4′), 8.63 (d, J=2.4 Hz, 1 H, H-6′), 9.19 (br s, 1 H, NH);MS (FAB) m/z 570 (MH⁺).

Preparative Example 42

[0367] Preparation of4-(5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxybenzamido)-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide (a compound of theformula (25) wherein R^(1 ═CH) ₂CH₃, R²═H, R³═CH₂CH₂CH₂F, R⁴═CH₂CH₂CH₃,R¹⁶=4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)

[0368] The titled compound was prepared as described in PreparativeExample 30 by using4-amino-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide and5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxybenzoicacid in place of 4-amino-3-ethyl-1-methylpyrrole-5-carboxamide and2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1ylsulfonyl)benzoicacid

[0369] yield: 83%

[0370] mp 162.5-163.5° C. (CH₂Cl₂/EtOAc/hexanes);

[0371] IR (neat) 3359(NH), 1651 (C═O), 1171 (SO₂)cm⁻¹;

[0372]¹H NMR (CDCl₃/TMS) δ1.08 (t, J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.41 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.72-2.02 (m, 6 H, OCH₂CH₂CH₃, CH₂CH₂CH₂F andNCH₂CH₂CH₂F), 2.45-2.58 (m, 8H, 2 NCH₂, CH₂CH₂CH₂F and NCH₂CH₂CH₂F),3.07 (m, 4 H, 2 SO₂NCH₂), 4.25 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 4.28 (t,J=7.2 Hz, 2 H, NCH₂CH₃), 4.43(dt, J=47.2 Hz, 6.0 Hz, 4 H, CH₂CH₂CH₂F andNCH₂CH₂CH₂F), 6.63 (s, 1 H, H-2), 7.16 (d, J=8.7 Hz, 1 H, H-3′), 7.89(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.63 (d, J=2.4 Hz, 1 H, H-6′), 9.18(br s, 1 H, NH); MS (FAB) m/z 584 (MH⁺).

Preparative Example 43

[0373] Preparation of4-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₂F,R⁴═CH₂CH₃, R¹⁶=4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)

[0374] The titled compound was prepared as described in PreparativeExample 30 by using4-amino-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide and2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)benzoicacid in place of 4-amino-3-ethyl-1-methylpyrrole-5-carboxamide and2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzoicacid

[0375] yield: 81%

[0376] IR (nest) 3355 (NH), 1662 (C═O), 1170 (SO₂) cm⁻¹;

[0377]¹H NMR (CDCl₃/TMS) δ1.49 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.57 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.81-1.98 (m, 2 H, CH₂CH₂CH₂F), 2.52 (t, J=7.5Hz, 2 H, CH₂CH₂CH₂F), 2.55 (t, J=5.4 Hz, 2 H, CH₂CH₂OH), 2.60 (dd, J=5.1Hz, 4.8 Hz, 4 H, 2 NCH₂), 3.08 (br dd, J=5.1 Hz, 4.8 Hz, 4 H, 2SO₂NCH₂), 3.58 (t, J=5.4 Hz, 2 H, CH₂CH₂OH), 4.27 (q, J=7.2 Hz, 2 H,NCH₂CH₃), 4.37 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.44 (dt, J=47.4 Hz, 6.0 Hz,2 H, CH₂CH₂CH₂F), 6.63 (s, 1 H, H-2), 7.16 (d, J=8.7 Hz, 1 H, H-3′),7.89 (dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.63 (d, J=2.7 Hz, 1 H, H-6′),9.19 (br s, 1 H, NH); MS (FAB) m/z 554 (MH⁺).

Preparative Example 44

[0378] Preparation of 4-(5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxybenzamido)-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₂F,R⁴═CH₂CH₂CH₃, R¹⁶=4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)

[0379] The titled compound was prepared as described in PreparativeExample 30 by using4-amino-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamide and5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxybenzoicacid in place of 4-amino-3-ethyl-1-methylpyrrole-5-carboxamide and2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzoicacid

[0380] yield: 65%

[0381] IR (neat) 3355 (NH), 1669 (C═O), 1165 (SO₂) cm⁻¹;

[0382]¹ H NMR (CDCl₃/TMS) δ1.08 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.41 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.80-2.02 (m, 4 H, CH₂CH₂CH₃ and CH₂CH₂CH₂F),2.51 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₂F), 2.56 (t, J=5.4 Hz, 2 H, CH₂CH₂OH),2.61 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 3.09 (br dd, J=5.1 Hz, 4.8 Hz,4 H, 2 SO₂NCH₂), 3.59 (t, J=5.4 Hz; 2 H, CH₂CH₂OH), 4.26 (q, J=6.6 H, 2H, CH₂CH₂CH₃), 4.27 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 4.44 (dt, J=47.1 Hz,5.7 Hz, 2 H, CH₂CH₂CH₂F), 6.63 (s, 1 H, H-2) 7.18 (d, J=8.7 Hz, 1 H,H-3′), 7.89 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.62 (d, J=2.4 Hz, 1 H,H-6′), 9.18 (br s, 1 H, NH); MS (FAB) m/z 568 (MH⁺).

Preparative Example 45

[0383] Preparation of4-(5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)-2-n-propoxybenzamido)-1-ethyl-3-n-propylpyrrole-5-carboxamide(a compound of the formula (25) wherein R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃, R¹⁶=4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)

[0384] The titled compound was prepared as described in PreparativeExample 30 by using 4-amino-1-ethyl-3-n-propylpyrrole-5-carboxamide and5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)-2-n-propoxybenzoic acid inplace of 4-amino-3-ethyl-1-methylpyrrole-5-carboxamide and2-ethoxy-5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)benzoic acid

[0385] yield: 83%

[0386] mp 128-129° C. (CH₂Cl₂/Et₂O);

[0387] IR (neat) 3359 (NH), 1653 (C═O), 1170 (SO₂) cm⁻¹;

[0388]¹H NMR (CDCl₃/TMS) δ0.92 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.09 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.41 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.48-1.60(m, 2 H, CH₂CH₂CH₃), 1.90-2.02 (m, 2 H, OCH₂CH₂CH₃), 2.33 (t, J=7.5 Hz,2 H, CH₂CH₂CH₃), 2.56 (t, J=5.4 Hz, 2 H, NCH₂CH₂O), 2.62 ((dd, J=4.8 Hz,4.5 Hz, 4 H, 2 NCH₂), 3.09 (br dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂),3.59 (t, J=5.4 Hz, 2 H, 2 NCH₂CH₂O), 4.27 (t, J=6.6 Hz, 2 H,OCH₂CH₂CH₃), 4.27 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 6.61 (s, 1 H, H-2), 7.18(d, J=8.7 Hz, 1 H, H-3′), 7.90 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.65(d, J=2.4 Hz, 1 H, H-6′), 9.16 (br, s, 1 H, NH); MS (FAB) m/z 550 (MH⁺).

Preparative Example 4546

[0389] Preparation of52-(2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[1,33,2-d]pyrimidin-74-one(a compound of the formula (9) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0390] A suspension of4-(2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide (5.01 g,15.21 mmol) and NaOH (3.04 g, 76.05 mmol) in a mixture of water (50 mL)and MeOH (100 ml) was heated at 80° C. under nitrogen atmosphere for 5h. The reaction mixture was cooled to room temperature, and MeOH wasremoved under vacuum. The resulting aqueous layer was acidified to aboutpH 9-10 with 1 N aqueous HCl solution, and was extracted with 2% MeOH inCHCl₃ (2×300 mL). Combined organic layer was dried (MgSO₄), filtered,and evaporated to dryness in vacuo to afford a yellow solid. The crudeproduct was purified by MPLC on silica gel (gradient elution: 1% MeOH inCHCl₃ followed by 2% MeOH in CHCl₃) to afford the titled compound (3.62g, 77%) as a white solid. Analytically pure compound was obtained bycrystallization from CHCl₃/Et₂O/hexanes.

[0391] mp 128.5-129° C.;

[0392] IR (neat) 3319 (NH), 1675 (C═O) cm⁻¹;

[0393]¹H NMR (CDCl₃/TMS) δ1.01 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.59 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.81 (m, 2 H, CH₂CH₂CH₃), 2.72 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 4.08 (s, 3 H, NCH₃), 4.27 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.86 (s, 1 H, H-2), 7.02 (d, J=8.4 Hz, 1 H, H-3′), 7.09-7.15(m, 1 H, H-5′), 7.41 (ddd, J=8.4 Hz, 7.2 Hz, 1.8 Hz, 1 H, H-4′), 8.49(dd, J=8.1 Hz, 1.8 Hz, 1 H, H-6′), 10.91 (br s, 1 H, NH); MS (FAB) m/z312 (MH⁺).

Preparative Example 4647

[0394] Preparation of 1-5-methyl-52-(2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (9) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0395] The titled compound was prepared as described in PreparativeExample 4546 by using1-methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamide inplace of 4-(2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0396] yield: 94%

[0397] mp 108-108.5° C. (CHCl₃/Et₂O/hexanes);

[0398] IR (neat) 3326 (NH), 1684 (C═O) cm⁻¹;

[0399]¹H NMR (CDCl₃/TMS) δ1.01 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.16 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.70-1.82 (m, 2 H, CH₂CH₂CH₃), 1.94-2.05 (m,2 H, OCH₂CH₂CH₃), 2.72 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.08 (s, 3 H,NCH₃), 4.16 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6.86 (s, 1 H, H-2), 7.02 (d,J=8.1 Hz, 1 H, H-3′), 7.12 (t, J=7.2 Hz, 1 H, H-5′), 7.41 (ddd, J=8.1Hz, 7.2 Hz, 1.8 Hz, 1 H, H-4′), 8.50 (dd, J=8.1 Hz, 1.8 Hz, 1 H, H-6′),10.94 (br s, 1 H, NH); MS (FAB) m/z 326 (MH⁺).

Preparative Example 4748

[0400] Preparation of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (2) wherein Y═Cl, R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0401] To a stirred and cooled chlorosulfonic acid (6 mL) in an ice bathunder nitrogen atmosphere was added portionwise52-(2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one (1.51 g, 4.85 mmol), andthe reaction mixture was stirred in an ice bath for 1 h. Then, themixture was warmed to room temperature gradually and stirring wascontinued for additional over 1 h at room temperature. Resulting mixturewas transferred dropwise to the well-stirred mixture of CHCl₃ (50 mL)and ice (50 g), and was extracted with 5% MeOH in CHCl₃ (2×100 mL).Combined extracts were dried (Na₂SO₄), filtered, and evaporated todryness under reduced pressure to give the desired sulfonyl chloride asa yellow solid. The crude product was solidified by dissolving in CHCl₃(20 mL), followed by diluting with diethyl ether (30 ml ) and hexanes(100 mL) to afford the titled compound (1.90 g, 96%) as a pale yellowsolid. Analytically pure compound was obtained by crystallization fromCHCl₃/Et₂O/hexanes.

[0402] mp 164.5-166° C. dec;

[0403] IR (neat) 3341 (NH), 1693 (C═O), 1174 (SO₂) cm⁻¹;

[0404]¹H NMR (CDCl₃/TMS) δ1.02 (t, J =7.2 Hz, 3 H, CH₂CH₂CH₃), 1.66 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.80 (m, 2 H, CH₂CH₂CH₃), 2.75 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 4.09 (s, 3 H NCH₃), 4.42 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.92 (s, 1 H, H-2), 7.20 (d, J =9.0 Hz, 1 H, H-3′), 8.08 (dd,J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 9.13 (d, J=2.4 Hz, 1 H, H-6′), 10.61 (brs, 1 H, NH); MS (FAB) m/z 392 (MH⁺—H₂O).

Preparative Example 4849

[0405] Preparation of52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one (a compound of the formula (2)wherein Y═Cl, R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃)

[0406] The titled compound was prepared as described in PreparativeExample 4748 by using15-methyl-52-(2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxyphenyl)-15-methyl-37-n-propyl-,1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0407] yield: 94%

[0408] mp 136° C. dec (CHCl₃/Et₂O);

[0409] IR (neat) 3330 (NH), 1665 (C═O) 1174 (SO₂) cm⁻¹;

[0410]¹H NMR (CDCl₃/TMS) δ1.02 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.18 (t,J=7.2 Hz, 3 H, OCH₂CH₂CH₃), 1.68-1.80 (m, 2 H, CH₂CH₂CH₃), 1.98-2.12 (m,2 H, OCH₂CH₂CH₃), 2.76 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.09 (s, 3 H,NCH₃), 4.30 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6.93 (s, 1 H, H-2), 7.21 (d,J=9.0 Hz, 1 H, H-3′), 8.07 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 9.11 (d,J=2.4 Hz, 1 H, H-6′); MS (FAB) m/z 424 (MH⁺).

Preparative Example 4950

[0411] Preparation of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide(a compound of the formula (12) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂F)

[0412] The titled compound was prepared as described in PreparativeExample 28 by using 2-(2-fluoroethoxy)benzoyl chloride in place of2-ethoxybenzoyl chloride.

[0413] yield: 67%

[0414] mp 132-132.5° C. (ethyl acetate/hexanes);

[0415] IR (neat) 3344, 3164 (NH), 1664, 1640 (C═O) cm⁻¹;

[0416]¹H NMR (CDCl₃/TMS) δ0.91 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.49-1.62(m, 2 H, CH₂CH₂CH₃), 2.33 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.85 (s, 3 H,NCH₃), 4.38-4.51 (m, 2 H, OCH₂CH₂F), 4.72-4.91 (m, 2 H, OCH₂CH₂F), 6.52(s, 1 H, H-2), 7.03 (d, J=8.1 Hz, 1 H, H-3′), 7.17 (td, J=8.1 Hz, 1.2Hz, 1 H, H-5′), 7.50-7.56 (m, 1 H, H-4′), 8.28 (dd, J=7.8 Hz, 1.8 Hz, 1H, H-6′), 9.11 (br s, 1 H, NH); MS (FAB) m/z 348 (MH⁺).

Preparative Example 51

[0417] Preparation of52-(2-(2-fluoroethoxy)phenyl)-15-methyl-37-n-propyl1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (9) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂F)

[0418] A suspension of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide(1.60 g 4.60 mmol) and potassium tert-butoxide (1.03 g, 9.21 mmol) intert-BuOH (25 mL) was heated at 60° C. under nitrogen atmosphere for 5h. The reaction mixture was cooled to room temperature, diluted withwater (25 ml ) and tert-BuOH was removed under vacuum. The resultingaqueous layer was acidified to about pH 5-6 with 1 N aqueous HClsolution, and was extracted with 5% McOH in CHCl₃ (2×100 mL). Combinedorganic layer was dried (MgSO₄), filtered, and evaporated to dryness invacuo to afford a yellow solid. The crude product was purified by MPLCon silica gel (1% MeOH in CHCl₃) to afford the titled compound (1.24 g,82%) as a pale yellow solid. Analytically pure compound was obtained bycrystallization from ethyl acetate/hexanes.

[0419] mp 116-117° C.;

[0420] IR (neat) 3348 (NH), 1676 (C═O) cm⁻¹;

[0421]¹H NMR (CDCl₃/TMS) δ1.01 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.70-1.78(m, 2 H, CH₂CH₂CH₃), 2.72 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.07 (s, 3 H,NCH₃), 4.36-4.48 (m, 2 H, OCH₂CH₂F), 4.77-4.96 (m, 2 H, OCH₂CH₂F), 6.86(s, 1 H, H-2), 7.02 (d, J=8.1 Hz, 1 H, H-3′), 7.17 (td, J=8.1 Hz, 0.9Hz, 1 H, H-5′), 7.39-7.46 (m, 1 H, H-4′), 8.44 (dd, J=8.1 Hz, 1.8 Hz, 1H, H-6′), 10.60 (br s, 1 H, NH); MS (FAB) m/z 330 (MH³⁰ ).

Preparative Example 5152

[0422] Preparation of52-(5-chlorosulfonyl-2-(2-fluoroethoxy)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (2) wherein Y═Cl, R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂F)

[0423] The titled compound was prepared as described in PreparativeExample 4748 by using52-(2-(2-fluoroethoxy)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin74-one.

[0424] yield: 85%

[0425] mp 156.5-157.5° C. (ethyl acetate/hexanes);

[0426] IR (neat) 3344 (NH), 1680 (C═O) 1174 (SO₂) cm⁻¹;

[0427]¹H NMR (CDCl₃/TMS) δ1.02 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.70-1.78(m, 2 H, CH₂CH₂CH₃), 2.75 (t, J=7.5 Hz, 2 H, CH₂ CH₂CH₃), 4.09 (s, 3 H,NCH₃), 4.51-4.63 (m, 2 H, OCH₂CH₂F), 4.84-5.02 (m, 2 H, OCH₂CH₂F), 6.92(s, 1 H, H-2), 7.23 (d, J=9.0 Hz, 1 H, H-3′), 8.10 (dd, J=9.0 Hz, 2.7Hz, 1 H, H-4′), 9.09 (d, J=2.7 Hz, 1 H, H-6′), 10.46 (br s, 1 H, NH); MS(FAB) m/z 428 (MH⁺).

Preparative Example 5453

[0428] Preparation ofN-(2-cyano-1-methyl-2-n-propylvinyl)-N-methylglycine ethyl ester (acompound of the formula (20) wherein R¹═R²═CH₃, R³═CH₂CH₂CH₃)

[0429] The titled compound was prepared as described in PreparativeExample 7 by using 3-cyano-2-hexanone in place of 2-cyanopentanal.

[0430] yield: 55%

[0431] IR (neat) 2181 (CN), 1743 (C═O) cm⁻¹;

[0432]¹H NMR (CDCl₃/TMS) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.30(t,J=7.2 Hz, 3 H, OCH₂CH₃), 1.46-1.58 (m, 2 H, CH₂CH₂CH₃), 1.90(s, 3 H,CH₃), 2.14(t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.11 (s, 3 H, NCH₃), 4.05(s, 2H, NCH₂CO), 4.22(q, J=7.2 Hz, 2 H, OCH₂CH₃)-Z isomer and 0.94(t, J=7.5Hz, 3 H, CH₂CH₂CH₃), 1.29 (t, J=7.2 Hz, 3 H, OCH₂CH₃), 1.52-1.65 (m, 2H, CH₂CH₂CH₃), 2.11 (d, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.19 (s, 3 H, CH₃),2.90 (s, 3 H, NCH₃), 3.80 (s, 2 H, NCH₂CO), 4.21 (q, J=7.2 Hz, 2 H,OCH₂CH₃)-E isomer; MS (FAB) m/z 225 (MH⁺).

Preparative Example 5354

[0433] Preparation ofN-(2-cyano-1-methyl-2-n-propylvinyl)-N-methylglycine amide (a compoundof the formula (19) wherein R¹═R²═CH₃, R³=n-propyl)

[0434] A suspension ofN-(2-cyano-1-methyl-2-n-propylvinyl)-N-methylglycine ethyl ester (2.03g, 9.05 mmol in 29% aqueous ammonia solution (13 mL) and MeOH (7 mL) wasstirred overnight at room temperature. The reaction mixture wasconcentrated in vacuo, and the aqueous layer was extracted with CH-Cl₃(40 mL×3). Combined organic layer was dried (Na₂SO₄), filtered and thefiltrate was evaporated to dryness under reduced pressure. Resultingresidue was purified by MPLC on silica gel (gradient elution: 1:1 ethylacetate/hexanes containing 1% Et₃N followed by 5% MeOH in CHCl₃) toafford the titled compound (1.03 g, 56%) as a yellowish oil.

[0435] IR (neat) 3323, 3208 (NH), 2180 (CN), 1670 (C═O) cm⁻¹;

[0436]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃),1.48-1.61(m, 2 H, CH₂CH₂CH₃), 1.84 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 1.93(s, 3 H, CH₃), 3.04 (s, 3 H, NCH₃) 3.79 (s, 2 H, NCH₂CO), 5.67 (br s, 1H, NH), 6.34 (br s, 1 H, NH)-Z isomer and 0.95(t, J=7.5 Hz, 3 H,CH₂CH₂CH₃), 1.45-1.58 (m, 2 H, CH₂CH₂CH₃), 2.15 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 2.20 (s, 3 H, CH₃), 2.86 (s, 3 H, NCH₃), 3.66 (s, 2 H,NCH₂CO), 5.76 (br s, 1 H, NH), 6.19 (br s, 1 H, NH)-E isomer; MS (FAB)m/z 196 (MH⁺).

Preparative Example 5455

[0437] Preparation of4-amino-1,2-dimethyl-3-n-propylpyrrole-5-carboxamide (a compound of theformula (15) wherein R¹═R²═CH₃, R³═CH₂CH₂CH₃)

[0438] The titled compound was prepared as described in PreparativeExample 21 by using N-(2-cyano-1-methyl-2-n-propylvinyl)-N-methylglycineamide in place of N-(2-cyano-2-n-propylvinyl)-N-methylglycine amide.

[0439] yield: 34%

[0440] mp 135° C. dec (CHCl₃/hexanes);

[0441] IR (neat) 3357, 3171 (NH₂), 1639 (C═O) cm⁻¹;

[0442]¹H NMR (CDCl₃/TMS) δ0.92 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃),1.39-1.51(m, 2 H, CH₂CH₂CH₃), 2.11 (s, 3 H, CH₃), 2.3 1 (t, J=7.5 Hz, 2H, CH₂CH₂CH₃), 3.23 (br s, 2 H, NH₂), 3.78 (s, 3 H, NCH₃), 6.16(br s, 2H, CONH₂); MS (FAB) m/z 196 (MH⁺).

Preparative Example 5556

[0443] Preparation of1,2-dimethyl-4-(2-ethoxybenzamido)-3-n-propylpyrrole-5-carboxamide (acompound of the formula (12) wherein R¹═R²═CH₃, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃)

[0444] The titled compound was prepared as described in PreparativeExample 28 by using 4-amino-1,2-dimethyl-3-n-propylpyrrole-5-carboxamidein place of 4-amino-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0445] yield: 73%

[0446] mp 171.5° C. dec (CHCl₃/Et₂O/hexanes);

[0447] IR (neat) 3348, 3148 (NH), 1649 (C═O) cm⁻¹;

[0448]¹H NMR (CDCl₃/TMS) δ0.87 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃),1.38-1.49(m, 2 H, CH₂CH₂CH₃), 1.51 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 2.17(s,3 H, CH₃), 2.33(t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.77 (s, 3 H, NCH₃), 4.29(q, J=6.9 Hz, 2 H, OCH₂CH₃), 7.04 (d, J=8.4 Hz, 1 H, H-3′), 7.09-7.14(m, 1 H, H-5′), 7.47-7.53(m,1 H, H-4′), 8.29 (dd, J=7.8 Hz, 1.8 Hz, 1 H,H-6′), 9.37 (br s, 1 H, NH); MS (FAB) m/z 344 (MH⁺).

Preparative Example 5657

[0449] Preparation of1,2-dimethyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamide (acompound of the formula (12) wherein R¹═R²═CH₃, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0450] The titled compound was prepared as described in PreparativeExample 28 by using 4-amino-1,2-dimethyl-3-n-propylpyrrole-5-carboxamideand 2-n-propoxybenzoyl chloride in place of4-amino-1-methyl-3-n-propylpyrrole-5-carboxamide and 2-ethoxybenzoylchloride.

[0451] yield: 69% p0 mp 188-189° C. (CHCl₃/Et₂O);

[0452] IR (neat) 3344, 3155 (NH), 1643 (C═O) cm⁻¹;

[0453]¹H NMR (CDCl₃/TMS) δ0.85 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.05 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.36-1.49 (m, 2 H, CH₂CH₂CH₃), 1.84-1.95 (m,2 H, OCH₂CH₂CH₃), 2.17 (s, 3 H, C₃), 2.32 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃),3.77 (s, 3 H, NCH₃), 4.17 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 7.04 (d, J=8.4Hz, 1 H, H-3′) 7.11 (td, J=7.8 Hz 1.2 Hz, 1 H, H-5′) 7.50 (ddd, J=8.4Hz, 7.8 Hz, 1.8 Hz, 1 H, H-4′), 8.29 (dd, J=7.8 Hz, 1.8 Hz, 1 H, H-6′),9.35 (br s, 1 H, NH), MS (FAB) m/z 358 (MH⁺).

Preparative Example 5758

[0454] Preparation of1,25,6-dimethyl-52-(2-ethoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (9) wherein R¹═R²═CH₃, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0455] The titled compound was prepared as described in PreparativeExample 5051 by using1,2-dimethyl-4-(2-ethoxybenzamido)-3-n-propylpyrrole-5-carboxamide inplace of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0456] yield: 94%

[0457] mp 130° C. dec (CHCl₃/Et₂O/hexanes);

[0458] IR (neat) 3175 (NH), 1653 (C═O) cm⁻¹;

[0459]¹H NMR (CDCl₃/TMS) δ0.97 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.59 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.62-1.73 (m, 2 H, CH₂CH₂CH₃), 2.30 (s, 3 H,CH₃), 2.69 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.03 (s, 3 H, NCH₃), 4.27 (q,J=6.9 Hz, 2 h, OCH₂CH₃), 7.01 (d, J=8.4 Hz, 1 H, H-3′), 7.12 (td, J=7.8Hz, 0.9 Hz, 1 H, H-5′), 7.37-7.43 (m, 1 H, H-4′), 8.49 (dd, J=7.8 Hz,1.8 Hz, 1 H, H-6′), 10.85 (br s, 1 H, NH); MS (FAB) m/z 326 (MH⁺).

Preparative Example 5859

[0460] Preparation of1,25,6-dimethyl-52-(2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (9) wherein R¹═R²═CH₃, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0461] The titled compound was prepared as described in PreparativeExample 5051 by using1,2-dimethyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamide inplace of4-(2-(2)-fluoroethoxy)benzamido-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0462] yield: 97%

[0463] mp 112-112.5° C. (CHCl₃/Et₂O/hexanes);

[0464] IR (neat) 3334 (NH), 1683 (C═O) cm⁻¹;

[0465]¹H NMR (CDCl₃/TMS) δ0.97 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.16(t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.63-1.75 (m, 2 H, CH₂CH₂CH₃), 1.94-2.06 (m,2 H, OCH₂CH₂CH₃), 2.30 (s, 3 H, CH₃), 2.70 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 4.03 (s, 3 H, NCH₃), 4.16(t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃),7.02(d, J=8.4 Hz, 1 H, H-3′), 7.12(td, J=7.8 Hz, 1.2 Hz, 1 H, H-5′),7.40(ddd, J=8.4 Hz, 7.8 Hz, 1.8 Hz, 1 H, H-4′), 8.50 (dd, J=7.8 Hz, 1.8Hz, 1 H, H-6′), 10.89 (br s, 1 H, NH); MS (FAB) m/z 340 (MH⁺).

Preparative Example 5060

[0466] Preparation of52-(5-chlorosulfonyl-2-ethoxyphenyl)-5,61,2-dimethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (2) wherein Y═Cl, R¹═R²═CH₃, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0467] The titled compound was prepared as described in PreparativeExample 4748 by using5,61,2-dimethyl-52-(2-ethoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0468] yield: 98% (crude)

[0469]¹H NMR (CDCl₃/TMS) δ0.97(t, J=7.5 Hz, 3 H, CH₂CH₂CH₃); 1.66 (t,J=6.9 Hz, 3 , OCH₂CH₃), 1.64-1.71 (m, 2 H, CH₃CH₂CH₃), 2.32 (s, 3 H,CH₃), 2.71(t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.04 (s, 3 H, NCH₃), 4.41 (q,J=6.9 Hz, 2 H, OCH₂CH₃), 7.19 (d, J=9.0 Hz, 1 H, H-3′), 8.06 (dd, J=9.0Hz, 2.7 Hz, 1 H, H-4′), 9.15 (d, J=2.7 Hz, 1 H, H-6′), 10.50 (br s, 1 H,NH); MS (FAB) m/z 424 (MH⁺).

Preparative Example 6061

[0470] Preparation of52-(5-chlorosulfony-2-n-propoxylphenyl)1,25,6-dimethyl-37-n-propyl-1,63,5-dihydro7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one (a compound of the formula (2)wherein Y═Cl, R¹═R²═CH₃, R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃)

[0471] The titled compound was prepared in a slightly impure form asdescribed in Preparative Example 4748 by using5,61,2-dimethyl-52-(2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0472] yield: 100% (crude)

[0473]¹H NMR (CDCl₃/TMS) δ0.97 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.18 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.64-1.77 (m, 2 H, CH₂CH₂CH₃), 2.00-2.10 (m,2 H, OCH₂CH₂CH₃), 2.33 (s, 3 H, CH₃), 2.73 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 4.04 (s, 3 H, NCH₃), 4.30 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃),7.20 (d, J=8.7 Hz, 1 H, H-3′), 8.07 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′),9.12 (d, J=2.4 Hz, 1 H, H-6′), 10.67 (br s, 1 H, NH).

Preparative Example 6162

[0474] Preparation of2-chloro-4-(2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide(a compound of the formula (12) wherein R¹═CH₃, R²═Cl, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0475] To a stirred solution of4-(2-ethoxybenzamido)-1-methyl-3n-propylpyrrole-5-carboxamide (1.02 g,3.09 mmol) in CH₂Cl₂ (35 mL) at −20° C. was added N-chlorosuccinimide(0.54 g, 4.04 mmol) and the mixture was stirred at −10° C. for 1 h.After standing overnight in a refrigerator (ca. −12° C.), the reactionmixture was stirred at 0° C. for additional 7 h. The reaction wasquenched by the addition of dilute Na₂S₂O₃ aqueous solution (3 mL) andwater (40 mL), and then the resulting mixture was extracted with CHCl₃(20 mL×4). Combined organic layer was dried (MgSO₄), filtered and thefiltrate was evaporated to dryness under vacuum to give an oily yellowresidue. The crude product was purified by MPLC on silica gel (gradientelution: 1:3 ethyl acetate/CHCl₃ followed by 1:2 ethyl acetate/CHCl₃) toafford the titled compound (0.72 g, 64%) as a white solid. Analyticallypure compound was obtained by crystallization from ethylacetate/hexanes.

[0476] mp 136.5-137° C.;

[0477] IR (neat) 3451, 3333 (NH), 1672, 1657 (C═O) cm⁻¹;

[0478]¹H NMR (CDCl₃/TMS) δ0.88 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.43-1.55(m, 2 H, CH₂CH₂CH₃), 1.52 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 2.38 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.83 (s, 3 H, NCH₃), 4.30 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 7.05 (d, J=8.4 Hz, 1 H, H-3′), 7.10-7.15 (m, 1 H, H-5′),7.49-7.55 (m, 1 H, H-4′), 8.29 (dd, J=7.8 Hz, 1.8 Hz, 1 H, H-6′), 9.40(br s, 1 H, NH); MS (FAB) m/z 364 (MH⁺).

Preparative Example 6263

[0479] Preparation of2-chloro-1-methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamide(a compound of the formula (12) wherein R¹═CH₃, R²═Cl, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0480] The titled compound was prepared as described in PreparativeExample 61 by using1-methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamide inplace of 4-(2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0481] yield: 82%

[0482] mp 139-140° C. (CHCl₃/Et₂O/hexanes);

[0483] IR (neat) 3333, 3155 (NH) 1650 (C═O) cm⁻¹;

[0484]¹H NMR (CDCl₃/TMS) δ0.87 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.05(t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.42-1.54 (m, 2 H, CH₂CH₂CH₃), 1.85-1.96 (m,2 H, OCH₂CH₂CH₃), 2.37 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.84(s, 3 H,NCH₃), 4.18 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 7.05 (d, J=8.4 Hz, 1 H,H-3′), 7.13(t, J=7.8 Hz, 1 H, H-5′), 7.49-7.55 (m, 1 H, H-4′), 8.29(dd,J=7.8 Hz, 1.8 Hz, 1 H, H-6′), 9.39 (br s, 1 H, NH); MS (FAB) m/z 378(MH⁺).

Preparative Example 6364

[0485] Preparation of26-chloro52-(2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one (a compound of the formula (9) whereinR¹═CH₃, R²═Cl, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃)

[0486] The titled compound was prepared as described in PreparativeExample 5051 by using2-chloro-4-(2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamidein place of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0487] yield: 70%

[0488] mp 145.5-146° C. (ethyl acetate/hexanes);

[0489] IR (neat) 3309 (NH), 1678 (C═O) cm⁻¹;

[0490]¹H NMR (CDCl₃/TMS) δ0.98 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.59 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.81 (m, 2 H, CH₂CH₂CH₃), 2.72 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 4.07 (s, 3 H, NCH₃), 4.27 (q, J=6.9 Hz, 2 H,OCH₂CH₃) 7.02 (d, J=8.1 Hz, 1 H, H-3′), 7.10-7.15 (m, 1 H, H-5′),7.39-7.45 (m, 1 H, H-4′), 8.49 (dd, J=8.1 Hz, 1.8 Hz, 1 H, H-6′), 11.00(br s, 1 H, NH); MS (FAB) m/z 346 (MH⁺).

Preparative Example 6465

[0491] Preparation of26-chloro-15-methyl-52-(2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (9) wherein R¹═CH₃, R²═Cl, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0492] The titled compound was prepared as described in PreparativeExample 5051 by using2-chloro-1-methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamidein place of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0493] yield: 91 %

[0494] mp 117-117.5° C. (Et₂O/hexanes);

[0495] IR (neat) 3315 (NH), 1687 (C═O) cm⁻¹;

[0496]¹H NMR (CDCl₃/TMS) δ0.98 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.17 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.68-1.80 (m, 2 H, CH₂CH₂CH₃), 1.95-2.06 (m,2 H, OCH₂CH₂CH₃), 2.73 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.07 (s, 3 H,NCH₃), 4.17 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 7.03 (d, J=8.4 Hz, 1 H,H-3′), 7.13 (td, J=8.1 Hz, 1.2 Hz, 1 H, H-5′), 7.40-7.46 (m, 1 H, H-4′),8.50 (dd, J=8.1 Hz, 1.8 Hz, 1 H. H-6′), 11.03 (br s, 1 H, NH); MS (FAB)m/z 360 (MH⁺).

Preparative Example 6566

[0497] Preparation of26-chloro-52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (2) wherein R¹═CH₃, R²═Y═Cl, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0498] The titled compound was prepared as described in PreparativeExample 4748 by using26-chloro-52-(2-ethoxyphenyl)-15-methyl-37-n-propyl1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one in place of52-(2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74one.

[0499] yield: 96%

[0500] mp 164° C. dec (Et₂O/hexanes);

[0501] IR (neat) 3343 (NH), 1691 (C═O) 1175 (SO₂) cm⁻¹;

[0502]¹H NMR (CDCl₃/TMS) δ0.98 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.66 (t,J=6.9 Hz, 3 h, OCH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 2.75 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 4.08 (s, 3 H, NCH₃), 4.42 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 7.21(d, J=9.02 Hz, 1 H, H-3′), 8.08 (dd, J=9.0 Hz, 2.4 Hz, 1H, H-4′), 9.12 (d, J=2.4 Hz, 1 H, H-6′), 10.65 (br s, 1 H, NH); MS (FAB)m/z 426 (M³⁰ -H₂O).

Preparative Example 6667

[0503] Preparation of26-chloro-52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (2) wherein R¹═CH₃, R²═Y═Cl, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0504] The titled compound was prepared as described in PreparativeExample 4748 by using26-chloro-15-methyl-52-(2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxyphenyl)-15-methyl37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0505] yield: 78%

[0506] mp 172.5° C. dec (CHCl₃/Et₂O/hexanes);

[0507] IR (neat) 3330 (NH), 1703 (C═O), 1182 (SO₂) cm⁻¹;

[0508]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.82 (m, 2 H, CH₂CH₂CH₃), 1.99-2.13 (m,2 H, OCH₂CH₂CH₃), 2.75 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.08 (s, 3 H,NCH₃), 4.31 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 7.22 (d, J=8.7 Hz, 1 H,H-3′), 8.09 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 9.13 (d, J=2.4 Hz, 1 H,H-6′), 11.40 (br s, 1 H, NH); MS (FAB) m/z 440 (M³⁰ -H₂O.

Preparative Example 6768

[0509] Preparation of2-bromo-4-(2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide)a compound of the formula (12) wherein R¹═CH₃, R²═Br, R³═CH₂CH₂CH₃;R⁴═CH₂CH₃)

[0510] To a stirred solution of4-(2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide (636 mg,1.93 mmol) and sodium acetate (238 mg, 2.90 mmol) in acetic acid (13 mL)at room temperature was added dropwise bromine (119 μl, 2.32 mmol) inacetic acid (6.5 mL) over a period of 10 minutes, and the mixture wasstirred for 10 minutes. The reaction mixture was diluted with water (10mL), and was extracted with Et₂O (10 mL×4). Combined organic layer wasdried (Na₂SO₄), filtered and the filtrate was evaporated to drynessunder vacuum. The crude residue was purified by MPLC on silica gel(gradient elution: 1% MeOH in CHCl₃ followed by 3% MeOH in CHCl₃) toafford the titled compound (544 mg, 69%) as a white solid. Analyticallypure compound was obtained by crystallization from CHCl₃/Et₂O/hexanes.

[0511] mp 152.5-153.5° C.;

[0512] IR (neat) 3453, 3192 (NH), 1663, 1644 (C═O) cm⁻¹;

[0513]¹H NMR (CDCl₃/TMS) δ0.88 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.43-1.58(m, 2 H, CH₂CH₂CH₃), 1.51 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 2.38 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.86 (s, 3 H, NCH₃), 4.30 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 7.04 (d, J=8.1 Hz, 1 H, H-3′), 7.09-7.14 (m, 1 H, H-5′),7.48-7.54 (m, 1 H, H-4′), 8.28 (dd, J=7.8 Hz, 1.8 Hz, 1 H, H-6′), 9.37(br s, 1 H, NH); MS (FAB) m/z 408 (M⁺).

Preparative Example 6869

[0514] Preparation of2-bromo-1-methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamide(a compound of the formula (12) wherein R¹═CH₃, R²═Br, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0515] The titled compound was prepared as described in PreparativeExample 6768 by using1-methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamide inplace of 4-(2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5 l-carboxamide.

[0516] yield: 85%

[0517] mp 142-143° C. (CHCl₃/Et₂O/hexanes);

[0518] IR (neat) 3332, 3149 (NH), 1648 (C═O) cm⁻¹;

[0519]¹H NMR (CDCl₃/TMS) δ0.87 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.05 (t,J=7.2 Hz, 3 H, OCH₂CH₂CH₃), 1.42-1.58 (m, 2 H, CH₂CH₂CH₃), 1.84-1.96 (m,2 H, OCH₂CH₂CH₃), 2.37 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.86 (s, 3 H,NCH₃), 4.18 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 7.05 (d, J=8.4 Hz, 1 H,H-3′), 7.12 (td, J=8.1 Hz, 0.9 Hz, 1 H, H-5′), 7.49-7.55 (m, 1 H, H-4′),8.29 (dd, J=8.1 Hz, 1.8 Hz, 1 H, H-6′), 9.41 (br s, 1 H, NH); MS (FAB)m/z 422 (M⁺).

Preparative Example 6970

[0520] Preparation of26-bromo-52-(2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo]4,33,2-d]pyrimidin-74-one (a compound of the formula (9) whereinR¹═CH₃, R²═Br, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃)

[0521] The titled compound was prepared as described in PreparativeExample 5051 by using2-bromo-4-(2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamidein place of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0522] yield: 100%

[0523] mp 152.5-1 53° C. (ethyl acetate/hexanes);

[0524] IR (neat) 3311 (NH)7 1679 (C═O) cm⁻¹;

[0525]¹H NMR (CDCl₃/TMS) δ0.98 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.59 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.69-1.8 (m, 2 H, CH₂CH₂CH₃), 2.72 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 4.09 (s, 3 H, NCH₃), 4.28 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 7.02 (d, J=8.4 Hz, 1 H, H-3′), 7.09-7.15 (m, 1 H, H-5′),7.39-7.45 (m, 1 H, H-4′), 8.49 (dd, J=7.8 Hz, 1.8 Hz, 1 H, H-6′), 10.96(br s, 1 H, NH); MS (FAB) m/z 311 (MH⁺—Br).

Preparative Example 7071

[0526] Preparation of26-bromo-15-methyl-52-(2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (9) wherein R¹═CH₃, R²═Br, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0527] The titled compound was prepared as described in PreparativeExample 5051 by using2-bromo-1-methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamidein place of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0528] yield: 90%

[0529] mp 110-112° C. (Et₂O/hexanes);

[0530] IR (neat) 3195 (NH), 1665 (C═O) cm⁻¹;

[0531]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.17 (t,J=7.2 Hz, 3 H, OCH₂CH₂CH₃), 1.68-1.81 (m, 2 H, CH₂CH₂CH₃), 1.94-2.06 (m,2 H, OCH₂CH₂CH₃), 2.72 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.09 (s, 3 H,NCH₃), 4.17 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 7.03 (d, J=8.1 Hz, 1 H,H-3′), 7.13 (td, J=8.1 Hz, 0.9 Hz, 1 H, H-5′), 7.40-7.46 (m. 1 H, H-4′),8.50 (dd, J=8.1 Hz, 1.8 Hz, 1 H, H-6′), 11.02 (br s, 1 H, NH); MS (FAB)m/z 404 (M⁺),

Preparative Example 7172

[0532] Preparation of26-bromo-52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onecompound of the formula (2) wherein Y═Cl, R¹═CH₃, R²═Br, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0533] The titled compound was prepared as described in PreparativeExample 4748 by using26-bromo-52-(2-ethoxyphenyl)-15-methyl-37n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin4-one in place of52-(2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0534] yield: 91%

[0535] mp 191-192° C. (Et₂O/hexanes);

[0536] IR (neat) 3331 (NH), 1696 (C═O), 1178 (SO₂) cm⁻¹;

[0537]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.66 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.67-1.80 (m, 2 H, CH₂CH₂CH₃), 2.75 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 4.10 (s, 3 H, NCH₃), 4.42 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 7.21(d, J=8.7 Hz, 1 H, H-3′), 8.08 (dd, J=8.7 Hz, 2.7 Hz, 1 H,H-4′), 9.12 (d, J=2.7 Hz, 1 H, H-6′), 10.66 (br s, 1 H, NH); MS (FAB)m/z 470, 472 (M⁺-H₂O).

Preparative Example 7273

[0538] Preparation of26-bromo-52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (2) wherein Y═Cl, R¹═CH₃, R²═Br,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃)

[0539] The titled compound as prepared as described in PreparativeExample 4748 by using26-bromo-15-methyl-52-(2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[yl4,33,2-d]pyrimidin-74-one in place of 52(2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0540] yield: 84%

[0541] mp 178° C. dec (CHCl₃/hexanes);

[0542] IR (neat) 3325 (NH), 1691 (C═O), 1178 (SO₂) cm³¹ ¹;

[0543]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.80 (m, 2 CH₂CH₂CH₃), 2.00-2.12 (m, 2H, OCH₂CH₂CH₃), 2.75 (t, J=7.5 Hz, CH₂CH₂CH₃), 4.10 (s, 3 H, NCH₃), 4.30(t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃), 7.22 (d, J=9.0 Hz, 1 H, H-3′), 8.08 (dd,J=9.0 Hz, 2.7 Hz, 1 H, H-4′), 9.14 (d, J=2.7 Hz, 1 H, H-6′), 10.66 (brs, 1 H, NH); MS (FAB) m/z 484, 486 (M⁺—H₂O).

Preparative Example 7374

[0544] Preparation of4-(2-ethoxybenzamido)-2-iodo-1-methyl-3-n-propylpyrrole-5-carboxamide (acompound of the formula (12) wherein R¹═CH₃, R²═1, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0545] To a stirred solution of4-(2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide (1.10 g,3.34 mmol) in benzene (30 mL) at 0° C. was added portionwise iodine(0.93 g, 3.67 mmol) and mercury oxide (0.62 g, 2.84 mmol) alternately,and the mixture was stirred for 2 h at 0° C. The reaction mixture wasdiluted with ethyl acetate (100 mL), washed once with dilute Na₂S₂O₃aqueous solution (100 mL), and the aqueous layer was further extractedwith ethyl acetate (100 mL). The combined organic layer was dried(MgSO₄), filtered and the filtrate was evaporated to dryness undervacuum. The crude residue was purified by MPLC on silica gel (20% ethylacetate in CHCl₃) to afford the titled compound (1.51 g, 99%) as a whitesolid. Analytically pure compound was obtained by crystallization fromethyl acetate/hexanes.

[0546] mp 157.5-158° C.;

[0547] IR (neat) 3338, 3186 (NH), 1660 (C═O) cm⁻¹;

[0548]¹H NMR (CDCl₃/TMS) δ0.90 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.42-1.54(m, 2 H, CH₂CH₂CH₃), 1.52 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 2.37 (t, J=7.5Hz, 2 , CH₂CH₂CH₃), 3.87 (s, 3 H, NCH₃), 4.30 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 7.05 (d, J=8.1 Hz, 1 H, H-3′), 7.10-7.15 (m, 1 H, H-5′),7.49-7.55 (m, 1 H, H-4′), 8.29 (dd, J=7.8 Hz, 2.1 Hz, 1 H, H-6′), 9.43(br s, 1 H, NH); MS (FAB) m/z 456 (MH⁺).

Preparative Example 7475

[0549] Preparation of2-iodo-1-methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamide(a compound of the formula (12) wherein R¹═CH₃, R²=1, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0550] The titled compound was prepared as described in PreparativeExample 7374 by using1-methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamide inplace of 4-(2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0551] yield: 82%

[0552] mp 169.5-170° C. (ethyl acetate/hexanes);

[0553] IR (neat) 3340, 3146 (NH), 1642 (C═O) cm⁻¹;

[0554]¹H NMR (CDCl₃/TMS) δ0.88 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.05 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.40-1.53 (m, 2 H, CH₂CH₂CH₃), 1.84-1.96 (m,2 H, OCH₂CH₂CH₃), 2.36 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.86 (s, 3 H,NCH₃), 4.18 (t, J=6.9 Hz, 2 H, OCH₂CH₂CH₃), 7.05 (d, J=8.4 Hz, 1 H-3′),7.09-7.15 (m, 1 H, H-5′), 7.52 (ddd, J=8.4 Hz, 7.5 Hz, 1.8 Hz, 1 H,H-4′), 8.28 (dd, J=8.0 Hz, 1.8 Hz, 1 H, H-6′), 9.42 (br s, 1 H, NH); MS(FAB) m/z 470 (MH⁺).

Preparative Example 7576

[0555] Preparation of52-(2-ethoxyphenyl)-26-iodo-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one (a compound of the formula (9) wherein R¹═CH₃,R²=1, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃)

[0556] The titled compound was prepared as described in PreparativeExample 5051 by using4-(2-ethoxybenzamido)-2-iodo-1-methyl-3-n-propylpyrrole-5-carboxamide inplace of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0557] yield: 81%

[0558] mp 178-178.5° C. (Et₂O/hexanes);

[0559] IR (neat) 3309 (NH), 1667 (C═O) cm⁻¹;

[0560]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.60 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 2.72 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 4.10 (s, 3 H, NCH₃), 4.28 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 7.02 (d, J=8.4 Hz, 1 H, H-3′), 7.13 (td, J=8.4 Hz, 1.2 Hz, 1H, H-5′), 7.39-7.45 (m, 1 H, H-4′), 8.49 (dd, J=7.8 Hz, 1.8 Hz, 1 H,H-6′), 10.96 (br s, 1 H, NH); MS (FAB) m/z 438 (MH⁺)

Preparative Example 7677

[0561] Preparation of26-iodo-15-methyl-52-(2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (9) wherein R¹═CH₃, R²═I, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0562] The titled compound was prepared as described in PreparativeExample 5051 by using2-iodo-1-methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamidein place of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0563] yield: 98%

[0564] mp 141-142° C. (CHCl₃/hexanes);

[0565] IR (neat) 3320 (NH), 1678 (C═O) cm³¹ ¹;

[0566]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.17 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 1.94-2.06 (m,2 H, OCH₂CH₂CH₃), 2.72 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.10 (s, 3 H,NCH₃), 4.17 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 7.03 (d, J=8.4 Hz, 1 H,H-3′), 7.10-7.15 (m, 1 H, H-5′), 7.40-7.45 (m, 1 H, H-4′), 8.50 (dd,J=7.8 Hz, 1.8 Hz, 1 H, H-6′), 10.98 (br s, 1 H, NH); MS (FAB) m/z 452(MH⁺).

Preparative Example 7778

[0567] Preparation of

[0568]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.42-1.68(m, 3 H, CH and 2 CH_(ax)), 1.61 (t, J=7.2 Hz, 3 H, OCH₂CH₃), 1.68-1.80(m, 2 H, CH₂CH₂CH₃), 1.84-1.93 (m, 2 H, 2 CH_(eq)), 2.29 (d, J=6.6 Hz, 2H, CH₂CN), 2.40 (td, J=11.7 Hz, 2.1 Hz, 2 H, 2 NCH_(ax)), 2.71 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.91 (br d, J=11.7 Hz, 2 H, 2 NCH_(eq)), 4.08 (s, 3H, NCH₃), 4.36 (q, J=7.2 Hz, 2 H, OCH₂CH₃), 6.89 (s, 1 H, H-2), 7.13 (d,J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.85 (d,J=2.7 Hz, 1 H, H-6′), 10.62 (br s, 1 H, NH); MS (FAB) m/z 498 (MH⁺)

Preparative Example 8081

[0569] Preparation of52-(5-(4-(cyanomethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(cyanomethyl)piperidinylpiperidin-1-yl)

[0570] The titled compound was prepared as described in PreparativeExample 7980 by using52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0571] yield: 96%

[0572] mp 194-194.5° C. (EtOAc/hexanes);

[0573] IR (neat) 3304 (NH), 2245 (CN), 1691 (C═O), 1166 (SO₂) cm⁻¹;

[0574]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.18 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.41-1.59 (m, 2 H, 2 CH_(ax)), 1.60-1.80 (m,3 H, CH and CH₂CH₂CH₃), 1.89 (br d, J=11.4 Hz, 2 H, 2 CH_(eq)),1.98-2.10 (m, 2 H, OCH₂CH₂CH₃), 2.29 (d, J=6.6 Hz, 2 H, CH₂CN), 2.40(td, J=12.0 1 Hz, 2.4 Hz, 2 H, 2 NCH_(ax)), 2.71 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 3.91 (br d, J=12.0 Hz, 2 H, 2 NCH_(eq)), 4.08 (s, 3 H,NCH₃), 4.25 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6.89 (s, 1 H, H-2), 7.14 (d,J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d,J=2.4 Hz, 1 H, H-6′), 10.65 (br s, 1 H, NH); MS (FAB) m/z 512 (MH⁺).

Preparative Example 8182

[0575] Preparation of52-(5-(4-(2-cyanoethyl)piperidinylpiperidin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,36,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-cyanoethyl)piperidinylpiperidin-1-yl)

[0576] The titled compound was prepared as described in PreparativeExample 7980 by using 4-(2-cyanoethyl)piperidine trifluoroacetic acid inplace of 4-(cyanomethyl)piperidine trifluoroacetic acid.

[0577] yield: 76%

[0578] mp 225-225.5° C. (EtOH/CHCl₃);

[0579] IR (neat) 3325 (NH), 2243 (CN), 1692 (C═O), 1162 (SO₂) cm⁻¹;

[0580]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.28-1.46(m, 3 H, CH and 2 CH_(ax)), 1.57-1.79 (m, 6 H, CH₂CH₂CH₃, CH₂CH₂CN and 2CH_(eq)), 1.64 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 2.33-2.39 (m, 4 H, CH₂CH₂CNand 2 NCH_(ax)), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.87 (br d, J=11.7Hz, 2 H, 2 NCH_(eq)), 4.08 (s, 3 H, NCH₃), 4.36 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.89 (s, 1 H, H-2), 7.13 (d, J=9.0 Hz, 1 H, H-3′), 7.81 (dd,J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d, J=2.4 Hz, 1 H, H-6′), 10.64 (brs, 1 H, NH), MS (FAB) m/z 512 (MH⁺).

Preparative Example 8283

[0581] Preparation of52-(5-(4-(2-cyanoethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-cyanoethyl)piperidinylpiperidin-1-yl)

[0582] The titled compound was prepared as described in PreparativeExample 7980 by using52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 4-(2-cyanoethyl)piperidine trifluoroacetic acid in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 4-(cyanomethyl)piperidine trifluoroacetic acid.

[0583] yield: 96%

[0584] mp 179-179.5° C. (EtOAc/hexanes);

[0585] IR (neat) 3330 (NH), 2243 (CN), 1692 (C═O), 1165 (SO₂) cm⁻¹;

[0586]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.30-1.42 (m, 2 H, 2 CH_(ax)), 1.57-1.79 (m7 H, CH, CH₂CH₂CN, CH₂CH₂CH₃ and 2 CH_(eq)), 1.98-2.10 (m, 2 H,OCH₂CH₂CH₃), 2.33-2.39 (m, 2 H, 2 NCH_(ax)), 2.35 (t, J=7.2 Hz, 2 H,CH₂CH₂CN), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.87 (br d, J=11.7 Hz, 2H, 2 NCH_(eq)), 4.08 (s, 3 H, NCH₃), 4.25 (t, J=6.3 Hz, 2 H,OCH₂CH₂CH₃), 6.89 (s, 1 H, H-2), 7.14 (d, J=8.7 Hz, 1 H, H-3′), 7.81(dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.87 (d, J=2.7 Hz, 1 H, H-6′), 10.69(br s, 1 H, NH); MS (FAB) m/z 526 (MH⁺).

Preparative Example 8384

[0587] Preparation of52-(2-ethoxy-5-(4-(ethoxycarbonylmethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(ethoxycarbonylmethyl)piperidinylpiperidin-1-yl)

[0588] The titled compound was prepared as described in PreparativeExample 7980 by using 4-(ethoxycarbonylmethyl)piperidine in place of4-(cyanomethyl)piperidine trifluoroacetic acid.

[0589] yield: 74%

[0590] mp 146-147° C. (EtOAc/hexanes);

[0591] IR (neat) 3316 (NH), 1738, 1695 (C═O), 1161 (SO₂) cm⁻¹;

[0592]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.22 (t,J=7.5 Hz, 3 H, CO₂CH₂CH₃), 1.31-1.46 (m, 2 H, 2 CH_(ax)), 1.63 (t, J=6.9Hz, 3 H, OCH₂CH₃), 1.67-1.80 (m, 5 H, CH, CH₂CH₂CH₃ and 2 CH_(eq)), 2.21(d, J=6.6 Hz, 2 H, CH₂CO₂), 2.39 (td, J=11.7 Hz, 2.1 Hz, 2 H, 2NCH_(ax)), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.83 (br d, J=11.7 Hz, 2H, 2 NCH_(eq)), 4.08 (s, 3 H, NCH₃), 4.09 (q, J=7.2 Hz, 2 H, CO₂CH₂CH₃),4.36 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 6.89 s, 1 H, H-2), 7.12 (d, J=9.0 Hz,1 H, H-3′), 7.81 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 8.85 (d, J=2.4 Hz, 1H, H-6′), 10.65 (br s, 1 H, NH); MS (FAB) m/z 545 (MH⁺).

Preparative Example 8485

[0593] Preparation of52-(5-(4-(ethoxycarbonylmethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(ethoxycarbonylmethyl)piperidinylpiperidin-1-yl)

[0594] The titled compound was prepared as described in PreparativeExample 7980 by using52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one and4-(ethoxycarbonylmethyl)piperidine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 4-(cyanomethyl)piperidine trifluoroacetic acid.

[0595] yield: 93%

[0596] mp 147.5-148° C. (EtOAc/CHCl₃);

[0597] IR (neat) 3335 (NH), 1732, 1669 (C═O), 1163 (SO₂) cm⁻¹;

[0598]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.22 (t, J=6.9 Hz, 3 H, CO₂CH₂CH₃),1.25-1.46 (m, 2 H, 2 CH_(ax)), 1.66-1.85 (m, 5 H, CH, CH₂CH₂CH₃ and 2CH_(eq)), 1.98-2.10 (m, 2 H, OCH₂CH₂CH₃), 2.21 (d, J=6.6 Hz, 2 H,CH₂CO₂), 2.33-2.45 (m, 2 H, 2 NCH_(ax)), 2.71 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 3.83 (br d, J=11.7 Hz, 2 H, 2 NCH_(eq)), 4.08 (s, 3 H,NCH₃), 4.09 (q, J=6.9 Hz, 2 H, CO₂CH₂CH₃), 4.25 (t, J=6.6 Hz, 2 H,OCH₂CH₂CH₃), 6.89 (s, 1 H, H-2), 7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.81(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.87 (d, J=2.4 Hz, 1 H, H-6′), 10.67(br s, 1 H, NH); MS (FAB) m/z 559 (MH⁺).

Preparative Example 8586

[0599] Preparation of52-(2-ethoxy-5-(4-(2-ethoxycarbonylethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-ethoxycarbonylethyl)piperidinylpiperidin-1-yl)

[0600] The titled compound was prepared as described in PreparativeExample 7880 by using 4-(2-ethoxycarbonylethyl)piperidine in place of4-(cyanomethyl)piperidine trifluoroacetic acid.

[0601] yield: 77%

[0602] mp 139.5-140° C. (EtOAc/hexanes);

[0603] IR (neat) 3322 (NH), 1734, 1694 (C═O), 1162 (SO₂) cm³¹ ¹;

[0604]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.17-1.44(m, 3 H, CH and 2 CH_(ax)), 1.22 (t, J=7.2 Hz, 3 H, CO₂CH₂CH₃),1.52-1.68 (m, 2 H, CH₂CH₂CO₂), 1.63 (t, J=7.2 Hz, 3 H, OCH₂CH₃),1.69-1.80 (m, 4 H, CH₂CH₂CH₃ and 2 CH_(eq)), 2.27 (t, J=7.5 Hz, 2 H,CH₂CH₂CO₂), 2.33 (br t, J=11.4 Hz, 2 H, 2 NCH_(ax)), 2.71 (t, J=7.5 Hz,2 H, CH₂CH₂CH₃), 3.83 (br d, J=11.4 Hz, 2 H, 2 NCH_(eq)), 4.08 (s, 3 H,NCH₃), 4.09 (q, J=7.2 Hz, 2 H, CO₂CH₂CH₃), 4.35 (q, J=7.2 Hz, 2 H,OCH₂CH₃), 6.89 (s, 1 H, H-2), 7.12 (d, J=8.7 Hz, 1 H, H-3′), 7.81 (dd,J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.85 (d, J=2.4 Hz, 1 H, H-6′), 10.64 (brs, 1 H, NH); MS (FAB) m/z 559 (MH⁺).

Preparative Example 8687

[0605] Preparation of52-(5-(4-(2-ethoxycarbonylethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-ethoxycarbonylethyl)piperidinylpiperidin-1-yl)

[0606] The titled compound was prepared as described in PreparativeExample 7980 by using52-(5-chlorosulfonyl-2n-propoxyphenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one and4-(2-ethoxycarbonylethyl)piperidine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 4-(cyanomethyl)piperidine trifluoroacetic acid.

[0607] yield: 80%

[0608] mp 134-135° C. (EtOAc/CHCl₃);

[0609] IR (neat) 3335, 3300 (NH), 1735, 1688 (C═O), 1163 (SO₂) cm⁻¹;

[0610]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.19(t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.22(t, J=7.2 Hz, 3 H, CO₂CH₂CH₃),1.21-1.40(m, 3 H, CH and 2 CH_(ax)), 1.49-1.62(m, 2 H, CH₂CH₂CO₂),1.67-1.80(m, 4 H, CH₂CH₂CH₃ and 2 CH_(eq)) 1.98-2.08 (m, 2 H,OCH₂CH₂CH₃), 2.27 (t, J=7.5 Hz, 2 H, CH₂CH₂CO₂), 2.29-2.38 (m, 2 H, 2NCH_(ax)), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.83 (br d, J=12.6 Hz, 2H, 2 NCH_(eq)), 4.082 (q, J=7.2 Hz, 2 H, CO₂CH₂CH₃), 4.083 (s, 3 H,NCH₃), 4.24(t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6.89 (s, 1 H, H-2), 7.13(d,J=8.7 Hz, 1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d,J=2.4 Hz, 1 H, H-6′), 10.66 (br s, 1 H, NH); MS (FAB) m/z 573 (MH⁺).

Preparative Example 8788

[0611] Preparation of52-(5-((S)-1-benzyloxycarbonyl-2-methylpropyl)aminosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is((S)-1-benzyloxycarbonyl-2-methylpropyl)amino)

[0612] The titled compound was prepared as described in PreparativeExample 7980 by using L-valine benzyl ester hydrochloride in place of4-(cyanomethyl)piperidine trifluoroacetic acid.

[0613] yield: 79%

[0614] mp 103-104° C. (EtOAc/Et₂O/hexanes);

[0615] IR (neat) 3327 (NH), 1741, 1674 (C═O), 1164 (SO₂) cm⁻¹;

[0616]¹H NMR (CDCl₃/TMS) δ0.86 (d, J=6.9 Hz, 3 H, CHCH₃), 0.97 (d, J=6.9Hz, 3 H, CHCH₃), 1.00 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.61 (t, J=6.9 Hz,3 H, OCH₂CH₃), 1.68-1.76 (m, 2 H, CH₂CH₂CH₃), 2.05-2.21 (m, 1 H,CH(CH₃)₂), 2.72 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.87 (dd, J=9.9 Hz, 5.1Hz, 1 H, NCHCO₂), 4.08 (s, 3 H, NCH₃), 4.29 (q, J=6.9 Hz, 2 H, OCH₂CH₃),4.89 (s, 2 H, OCH₂Ph), 5.27 (d, J=9.9 Hz, 1 H, SO₂NH), 6.89 (s, 1 H,H-2), 7.00 (d, J=8.7 Hz, 1 H, H-3′), 7.10-7.26 (m, 5 H, ArH), 7.84 (dd,J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.92 (d, J=2.4 Hz, 1 H, H-6′), 10.64 (brs, 1 H, NH); MS (FAB) m/z 581 (MH⁺).

Preparative Example 8889

[0617] Preparation of52-(5-((S)-1-benzyloxycarbonyl-2-methylpropyl)aminosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is((S)-1-benzyloxycarbonyl-2-methylpropyl)amino)

[0618] The titled compound was prepared as described in PreparativeExample 7980 by using52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand L-valine benzyl ester hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 4-(cyanomethyl)piperidine trifluoroacetic acid.

[0619] yield: 82%

[0620] mp 126-127° C. (EtOAc/Et₂O/hexanes);

[0621] IR (neat) 3330 (NH), 1741, 1675 (C═O), 1165 (SO₂) cm³¹ ¹;

[0622]¹H NMR (CDCl₃/TMS) δ0.86 (d, J=6.9 Hz, 3 H, CHCH₃), 0.97 (d, J=6.9Hz, 3 H, CHCH₃), 1.01 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.18 (t, J=7.5 Hz,3 H, OCH₂CH₂CH₃), 1.69-1.78 (m, 2 H, CH₂CH₂CH₃), 1.98-2.14 (m, 3 H,OCH₂CH₂CH₃ and CH(CH₃)₂), 2.73 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.88 (dd,J=9.9 Hz, 5.1 Hz, 1 H, NCHCO₂) 4.09 (s, 3 H, NCH₃), 4.19 (t, J=6.6 Hz, 2H, OCH₂CH₂CH₃), 4.89 (s, 2 H, OCH₂Ph), 5.19 (d, J=9.9 Hz, 1 H, SO₂NH),6.89 (s, 1 H, H-2) 7.02 (d, J=8.7 Hz, 1 H, H-3′), 7.11-7.33 (m, 5 H,ArH), 7.85 (dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.95 (d, J=2.7 Hz, 1 H,H-6′), 10.67 (br s, 1 H, NH); MS (FAB) m/z 595 (MH⁺).

Preparative Example 8990

[0623] Preparation of4-(2-ethoxy-5-nitrobenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide(a compound of the formula (13) wherein R⁵═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0624] The titled compound was prepared as described in PreparativeExample 28 by using 2-ethoxy-5-nitrobenzoyl chloride in place of2-ethoxybenzoyl chloride.

[0625] yield: 96%

[0626] mp 227-227.5° C. (CHCl₃/Et₂O);

[0627] IR (neat) 3447, 3299 (NH), 1657, 1639 (C═O), 1341, 1288 (NO₂)cm⁻¹;

[0628]¹H NMR (CDCl₃/TMS) δ0.92 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.46-1.57(m, 2 H, CH₂CH₂CH₃), 1.60 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 2.33 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.85 (s, 3 H, NCH₃), 4.42 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.54 (s, 1 H, H-2), 7.16 (d, J=9.0 Hz, 1 H, H-3′), 8.39 (dd,J=9.0 Hz, 2.7 Hz, 1 H, H-4′), 9.13 (br s, 1 H, NH), 9.16 (d, J=2.7 Hz, 1H, H-6′), MS (FAB) m/z 375 (MH⁺).

Preparative Example 9091

[0629] Preparation of4-(5-nitro-2-n-propoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide(a compound of the formula (13) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0630] The titled compound was prepared as described in PreparativeExample 28 by using 5-nitro-2-n-propoxybenzoyl chloride in place of2-ethoxybenzoyl chloride.

[0631] yield: 94%

[0632] mp 224-224.5° C. (CHCl₃/Et₂O);

[0633] IR (neat) 3388, 3186 (NH), 1659, 1639 (C═O), 1341, 1277 (NO₂)cm³¹ ¹;

[0634]¹H NMR (CDCl₃/TMS) δ0.91 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.09 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.47-1.59 (m, 2 H, CH₂CH₂CH₃), 1.91-2.03 (m,2 H, OCH₂CH₂CH₃), 2.32 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.85 (s, 3 H,NCH₃), 4.30 (t, J=6.9 Hz, 2 H, OCH₂CH₂CH₃), 6.54 (s, 1 H, H-2), 7.16 (d,J=8.7 Hz, 1 H, H-3′), 8.39 (dd, J=8.7 Hz, 3.0 Hz, 1 H, H-4′), 9.12 (brs, 1 H, NH), 9.16 (d, J=3.0 Hz, 1 H, H-6′); MS (FAB) m/z 389 (MH⁺).

Preparative Example 9192

[0635] Preparation of52-(2-ethoxy-5-nitrophenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (10) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0636] The titled compound was prepared as described in PreparativeExample 5051 by using4-(2-ethoxy-5-nitrobenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamidein place of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0637] yield: 77%

[0638] mp 211-211.5° C. (CHCl₃/Et₂O);

[0639] IR (neat) 3327 (NH), 1684 (C═O), 1341, 1268 (NO₂) cm³¹ ¹;

[0640]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.37 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.58-1.70 (m, 2 H, CH₂CH₂CH₃), 2.59 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.99 (s, 3 H, NCH₃), 4.27 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 7.23 (s, 1 H, H-2), 7.36 (d, J=9.3 Hz, 1 H, H-3′), 8.35 (dd,J=9.3 Hz, 3.0 Hz, 1 H, H-4′), 8.43 (d, J=3.0 Hz, 1H, H-6′), 11.75 (br s,1 H, NH): MS (FAB) m/z 357 (MH⁺).

Preparative Example 9293

[0641] Preparation of15-methyl-52-(5-nitro-2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (10) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0642] The titled compound was prepared as described in PreparativeExample 5051 by using1-methyl-4-(5-nitro-2-n-propoxybenzamido)-3-n-propylpyrrole-5-carboxamidein place of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0643] yield: 95%

[0644] mp 181.5° C. dec (CHCl₃/Et₂O);

[0645] IR (neat) 3324 (NH), 1689 (C═O), 1345, 1273 (NO₂) cm⁻¹;

[0646]¹H NMR (CDCl₃/TMS) δ1.02 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.68-1.82 (m, 2 H, CH₂CH₂CH₃), 1.91-2.12 (m,2 H, OCH₂CH₂CH₃), 2.75 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.09 (s, 3 H,NCH₃), 4.28 (t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃), 6.91 (s, 1 H, H-2), 7.12 (d,J=9.3 Hz, 1 H, H-3′), 8.30 (dd, J=9.3 Hz, 3.0 Hz, 1 H, H-4′), 9.36 (d,J=3.0 Hz, 1 H, H-6′), 10.61 (br s, 1 H, NH); MS (FAB) m/z 371 (MH⁺).

Preparative Example 9394

[0647] Preparation of52-(5-amino-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (3) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0648] A mixture of52-(2-ethoxy-5-nitrophenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(443 mg, 1.21 mmol) and 5% Pd/C (43 mg) in THF (10 mL) and EtOH (10 ml )was purged with hydrogen gas three times and stirred vigorously underhydrogen atmosphere (1 atm; a balloon) at room temperature for 5 h. Themixture was filtered through a Celite pad, and the filtrate wasevaporated to dryness under reduced pressure. The resulting yellowresidue was purified by MPLC on silica gel (1% MeOH in CHCl₃) to affordthe titled compound (388 mg, 98%) as a pale yellow solid. Analyticallypure compound was obtained by crystallization from EtOAc/hexanes.

[0649] mp 165.5-166° C.;

[0650] IR (neat) 3542, 3329, 3297 (NH), 1647 (C═O) cm⁻¹;

[0651]¹H NMR (CDCl₃/TMS) δ1.01 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.53 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.80 (m, 2 H, CH₂CH₂CH₃), 2.72 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 4.07 (s, 3 H, NCH₃), 4.16 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.76 (dd, J=9.0 Hz, 3.0 Hz, 1 H, H-4′), 6.85 (s, 1 H, H-2),6.87 (d, J=9.0 Hz, 1 H, H-3′), 7.85 (d, J=3.0 Hz, 1 H, H-6′); MS (FAB)m/z 327 (MH⁺).

Preparative Example 9495

[0652] Preparation of52-(5-amino-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (3) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0653] The titled compound was prepared as described in PreparativeExample 9394 by using15-methyl-2-(5-nitro-2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-nitrophenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0654] yield: 63%

[0655] mp 94-96.5° C. (CH₂Cl₂/MeOH/Et₂O);

[0656] IR (neat) 3505, 3439, 3312 (NH), 1676 (C═O) cm⁻¹;

[0657]¹H NMR (DMSO-d₆) δ1.19 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.23 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃) 1.84-2.03 (m, 4 H, CH₂CH₂CH₃ and OCH₂CH₂CH₃),2.84 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.20 (t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃),4.22 (s, 3 H, NCH₃), 5.13 (br s, 2 H, NH₂), 6.94 (dd, J=8.7 Hz, 3.0 Hz,1 H, H-4′), 7.15 (d, J=8.7 Hz, 1 H, H-3′), 7.44 (s, 1 H, H-2), 7.45 (d,J=3.0 Hz, 1 H, H-6′), 11.57 (br s, 1 H, NH); MS (FAB) m/z 341 (MH⁺).

Preparative Example 9596

[0658] Preparation of4-(5-bromo-2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide(a compound of the formula (14) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R³═CH₂CH₃)

[0659] The titled compound was prepared as described in PreparativeExample 28 by using 5-bromo-2-ethoxybenzoyl chloride in place of2-ethoxybenzoyl chloride.

[0660] yield: 98%

[0661] mp 158-159° C. (EtOAc/Et₂O/hexanes);

[0662] IR (neat) 3445, 3174 (NH), 1656 (C═O) cm⁻¹;

[0663]¹H NMR (CDCl₃/TMS) δ0.92 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.47-1.59(m, 2 H, CH₂CH₂CH₃), 1.52 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 2.32 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.85 (s, 3 H, NCH₃), 4.27 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.52 (s, 1 H, H-2), 6.93 (d, J=9.0 Hz, 1 H, H-3′), 7.59 (dd,J=9.0 Hz, 2.7 Hz, 1 H, H-4′), 8.40 (d, J=2.7 Hz, 1 H, H-6′), 9.28 (br s,1 H, NH); MS (FAB) m/z 391 (MH⁺—H₂O).

Preparative Example 9697

[0664] Preparation of4-(5-bromo-2-n-propoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide(a compound of the formula (14) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0665] The titled compound was prepared as described in PreparativeExample 28 by using 5-bromo-2-n-propoxybenzoyl chloride in place of2-ethoxybenzoyl chloride.

[0666] yield: 89%

[0667] mp 148-150° C. (CHCl₃/hexanes);

[0668] IR (neat) 3315, 3174 (NH), 1659, 1642 (C═O) cm⁻¹;

[0669]¹H NMR (CDCl₃/TMS) δ0.91 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.05 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.46-1.56 (m, 2 H, CH₂CH₂CH₃), 1.85-1.97 (m,2 H, OCH₂CH₂CH₃), 2.31 (t. J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.84 (s, 3 H,NCH₃), 4.16 (t, J=6.9 Hz, 2 H, OCH₂CH₂CH₃), 6.53 (s, 1 H, H-2), 6.94 (d,J=9.0 Hz, 1 H, H-3′), 7.59 (dd, J=9.0 Hz, 2.7 Hz, 1 H, H-4′), 8.40 (d,J=2.7 Hz, 1 H, H-6′), 9.28 (br s, 1 H, NH); MS (FAB) m/z 405 (MH⁺—H₂O).

Preparative Example 9798

[0670] Preparation of52-(5-bromo-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (11) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0671] The titled compound was prepared as described in PreparativeExample 5051 by using4-(5-bromo-2-ethoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamidein place of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0672] yield: 80%

[0673] mp 151.5-152° C. (EtOAc/Et₂O/hexanes);

[0674] IR (neat) 3318 (NH), 1690 (C═O) cm³¹ ¹;

[0675]¹H NMR (CDCl₃/TMS) δ1.02 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.59 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.67-1.80 (m, 2 H, CH₂CH₂CH₃), 2.73 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 4.08 (s, 3 H, NCH₃), 4.25 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.87 (s, 1H, H-2), 6.90 (d, J=9.0 Hz, 1 H, H-3′), 7.49 (dd,J=9.0 Hz, 2.7 Hz, 1 H, H-4′), 8.59 (d, J=2.7 Hz, 1 H, H-6′), 10.79 (brs, 1 H, NH); MS (FAB) m/z 390 (MH³⁰ ).

Preparative Example 9899

[0676] Preparation of52-(5-bromo-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (11) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0677] The titled compound was prepared as described in PreparativeExample 5051 by using4-(5-bromo-2-n-propoxybenzamido)-1-methyl-3-n-propylpyrrole-5-carboxamidein place of4-(2-(2-fluoroethoxy)benzamido)-1-methyl-3-n-propylpyrrole-5-carboxamide.

[0678] yield: 76%

[0679] mp 118-119° C. (EtOAc/hexanes);

[0680] IR (neat) 3324 (NH), 1696 (C═O) cm⁻¹;

[0681]¹NMR (CDCl₃/TMS) δ1.02 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.15 (t,J=7.2 Hz, 3 H, OCH₂CH₂CH₃), 1.68-1.80 (m, 2 H, CH₂CH₂CH₃), 1.93-2.05 (m,2 H, OCH₂CH₂CH₃), 2.73 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.08 (s, 3 H,NCH₃), 4.14 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6.88 (s, 1 H, H-2), 6.91 (d,J=8.7 Hz, 1 H, H-3′), 7.50 (dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.60 (d,J=2.7 Hz, 1 H, H-6′), 10.82 (br s, 1 H, NH): MS (FAB) m/z 404 (MH³⁰ ).

Preparative Example 99100

[0682] Preparation of52-(5-cyano-2-ethoxyphenyl)-1-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (4) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃)

[0683] A mixture of52-(5-bromo-2-ethoxyphenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(560 mg, 1.43 mmol) and copper(I) cyanide (2.57 g, 28.7 mmol) in1-methyl-2-pyrrolidinone (10 mL) was heated at 190° C. for 5 h. and thencooled to room temperature. The reaction mixture was poured into acooled mixture of 29% aqueous ammonia solution (70 mL) and water (140mL) in an ice bath, and the resulting deep blue suspension was stirredfor 1 h in an ice bath. The mixture was extracted with CHCl₃ (80 mL×3),the combined organic layer was dried (MgSO₄), filtered and the filtratewas evaporated to dryness under reduced pressure. The crude residue wassolidified from Et₂O/hexanes, and the resulting solid was purified byMPLC on silica gel (1% MeOH in CHCl₃) to afford the titled compound (376mg, 78%) as a pale yellow solid. Analytically pure compound was obtainedby crystallization from CHCl₃/Et₂O.

[0684] mp 232.5-233° C.;

[0685] IR (neat) 3329 (NH), 2228 (CN), 1692 (C═O) cm⁻¹;

[0686]¹H NMR (CDCl₃/TMS) δ1.02 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.63 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.79 (m, 2 H, CH₂CH₂CH₃), 2.73 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 4.08 (s, 3 H, NCH₃), 4.35 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.90 (s, 1 H, H-2), 7.09 (d, J=8.7 Hz, 1 H, H-3′), 7.69 (dd,J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.82 (d, J=2.4 Hz, 1 H, H-6′), 10.62 (brs, 1 H, NH); MS (FAB) m/z 337 (MH⁺).

Preparative Example 100101

[0687] Preparation of2-(5-cyano-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (4) wherein R¹═C₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃)

[0688] The titled compound was prepared as described in PreparativeExample 99100 by using52-(5-bromo-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(5-bromo-2-ethoxyphenyl)-1-5-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0689] yield: 84%

[0690] mp 179-180.5° C. (CHCl₃/hexanes);

[0691] IR (neat) 3333 (NH), 2225 (CN), 1689 (C═O) cm⁻¹;

[0692]¹H NMR (CDCl₃/TMS) δ1.02 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.18(t,J=7.2 Hz, 3 H, OCH₂CH₂CH₃), 1.68-1.80 (m, 2 H, CH₂CH₂CH₃), 1.98-2.09 (m,2 H, OCH₂CH₂CH₃), 2.73 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.08(s, 3 H,NCH₃), 4.24 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6.90 (s, 1 H, H-2), 7.10 (d,J=9.0 Hz, 1 H, H-3′), 7.69 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 8.83(d,J=2.4 Hz, 1 H, H-6′), 10.66(br s, 1 H, NH); MS (FAB) m/z 351 (MH⁺).

Example 1

[0693] Preparation of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is 4-methylpiperazinylpiperazin-1-yl)

[0694] To a mixture of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(170 mg, 0.41 mmol) and 1-methylpiperazine (69 μL, 0. 62 mmol) inanhydrous CH₂CH₂ (10 ml ) or EtOH (10 ml) was added triethylamine (115μL, 0.83 mmol), and the mixture was stirred at room temperature undernitrogen atmosphere for 1-12 h. The reaction mixture was evaporated todryness under reduced pressure, and the resulting yellow residue waspurified by MPLC on silica gel (gradient elution: 2% MeOH in CHCl₃followed by 3% MeOH in CHCl₃) to afford the titled compound (161 mg,82%) as a yellowish solid. Analytically pure compound was obtained bycrystallization from EtOAc/hexanes.

[0695] mp 220.5-221° C.

[0696] IR (neat) 3334 (NH), 1678 (C═O), 1172 (SO₂) cm⁻¹;

[0697]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.63 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃) 2.27 (s, 3 H,NCH₃), 2.49 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 3.11 (dd, J=5.1 Hz, 4.08 Hz, 4 H, 2 SO₂NCH₃), 4.08 (s, 3 H,NCH₃), 4.35 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 6.88 (s, 1 H, H-2), 7.12 (d,J=8.7 Hz, 1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.87 (d,J=2.4 Hz, 1 H, H-6′), 10.60 (br s, 1 H, NH); MS (FAB) m/z 474 (MH⁺).

Example 2

[0698] Preparation of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-methylpiperazinylpiperazin-1-yl)

[0699] To a solution of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(77 mg, 0.16 mmol) in anhydrous CH₂Cl₂ (2 mL) was added 1 M HCl ethersolution (180 μL, 0.18 mmol) at room temperature under nitrogenatmosphere, and the solution was stirred for about 10 minutes. Thereaction mixture was poured slowly into anhydrous ether (50 mL), and theresulting white precipitates were collected by filtration. The filteredsolid was dissolved in H₂O (20 mL), filtered through a membrane filter(0.45 μm), and the filtrate was freeze-dried to afford the titledcompound (79 mg, 95%) as an off-white floppy solid.

[0700] mp 131.5° C. dec;

[0701] IR (neat) 3334 (NH), 1686 (C═O), 1163 (SO₂) cm⁻¹;

[0702]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.36 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.58-1.70 (m 2 H, CH₂CH₂CH₃), 2.58 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 2.66-2.83 (br s, 5 H, NCH₃ and 2 SO₂NCH_(ax)),3.05-3.22 (m, 2 H, 2 SO₂NCH_(eq)) 3.35-3.54 (m, 2 H, 2 HNCH_(ax)),3.72-3.88 (m, 2 H, 2 HNCH_(eq)), 3.99 (s, 3 H, NCH₃), 4.24 (q, J=6.9 Hz,2 H, OCH₂CH₃), 7.23 (s, 1 H, H-2), 7.41 (d, J=9.0 Hz, 1 H, H-3′) 7.86(dd, J=9.0 Hz, 2.7 Hz, 1 H, H-4′), 7.97 (d, J=2.7 Hz, 1 H, H-6′), 10.58(br s, 1 H, NH⁺), 11.75 (br s, 1 H, NH).

Example 3

[0703] Preparation of52-(5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is 4-methylpiperazinylpiperazin-1-yl)

[0704] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo-[4,33,2-d]pyrimidin-74-one.

[0705] yield: 81%

[0706] mp 183-183.5° C. (EtOAc/hexanes);

[0707] IR (neat) 3297 (NH), 1695 (C═O), 1171 (SO₂) cm⁻¹;

[0708]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.18 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 1.98-2.07 (m,2 H, OCH₂CH₂CH₃), 2.27 (s, 3 H, NCH₃), 2.49 (dd, J=5.1 Hz, 4.8 Hz, 4 H,2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.11 (dd, J=5.1 Hz, 4.8 Hz,4 H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.24 (t, J=6.6 Hz, 2 H,OCH₂CH₂CH₃), 6.88 (s, 1 H, H-2), 7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.81(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.88 (d, J=2.4 Hz, 1 H, H-6′), 10.67(br s, 1 H, NH); MS (FAB) m/z 488 (MH³⁰ ).

Example 4

[0709] Preparation of52-(5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo-[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-methylpiperazinylpiperazin-1-yl)

[0710] The titled compound was prepared as described in Example 2 byusing52-(5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0711] yield: 93%

[0712] mp 124.5° C. dec;

[0713] IR (neat) 3348 (NH), 1680 (C═O), 1167 (SO₂) cm⁻¹;

[0714]¹H- NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 0.97 (t,J=7.2 Hz, 3 H, OCH₂CH₂CH₃), 1.57-1.70 (m, 2 H, CH₂CH₂CH₃), 1.70-1.81 (m,2 H, OCH₂CH₂CH₃), 2.58 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.75 (s, 3 H,NCH₃), 2.76-2.80 (m, 2 H, 2 SO₂NCH_(ax)), 3.08-3.22 (m, 2 H, 2SO₂NCH_(eq)), 3.35-3.50 (m, 2 H, 2 ⁺HNCH_(ax)), 3.81 (br d, J=12.3 Hz, 2H, 2 ⁺HNCH_(eq)), 3.99 (s, 3 H, NCH₃), 4.14 (t, J=6.6 Hz, 2 H,OCH₂CH₂CH₃), 7.24 (s, 1 H, H-2), 7.42 (d, J=9.0 Hz, 1 H, H-3′), 7.87(dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 7.98 (d, J=2.4 Hz, 1 H, H-6′), 10.93(br s, 1 H, NH⁺), 11.76 (br s, 1 H, NH).

Example 5

[0715] Preparation of52-(2-ethoxy-5-(4-ethylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is 4-ethylpiperazinylpiperazin-1-yl)

[0716] The titled compound was prepared as described in Example 1 byusing 1-ethylpiperazine in place of 1-methylpiperazine.

[0717] yield: 89%

[0718] mp 200-200.5° C. (CHCl₃/EtOAc/hexanes);

[0719] IR (neat) 3332 (NH) 1680 (C═O), 1172 (SO₂) cm⁻¹;

[0720]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.02(t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.63 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.67-1.77 (m,2 H, CH₂CH₂CH₃), 2.40 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 2.53(dd, J=5.1 Hz,4.8 Hz, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.11(dd, J=5.1Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.35 (q, J=6.9 Hz, 2H, OCH₂CH₃), 6.88 (s, 1 H, H-2), 7.12 (d, J=9.0 Hz, 1 H, H-3′), 7.80(dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 8.87 (d, J=2.4 Hz, 1H, H-6′), 10.62(br s, 1 H, NH); MS (FAB) m/z 488 (MH⁺).

Example 6

[0721] Preparation of52-(2-ethoxy-5-(4-n-propylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is 4-n-propylpiperazinylpiperazin-1-yl)

[0722] The titled compound was prepared as described in Example 1 byusing 1-n-propylpiperazine in place of 1-methylpiperazine.

[0723] yield: 76%

[0724] mp 202.5° C. dec (CHCl₃/Et₂O/hexanes);

[0725] IR (neat) 3332 (NH), 1677 (C═O), 1170 (SO₂) cm⁻¹;

[0726]¹H NMR (CDCl₃/TMS) 0.90 (t, J=7.5 Hz, 3 H, NCH₂CH₂CH₃), 0.99 (t,J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.37-1.50 (m, 2 H, NCH₂CH₂CH₃), 1.63 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.64-1.77 (m, 2 H, CH₂CH₂CH₃), 2.28 (dd, J=7.8Hz, 7.5 Hz, 2 H, NCH₂CH₂CH₃), 2.52 (dd, J=4.8 Hz, 3.9 Hz, 4 H, 2 NCH₂),2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.10 (dd, J=4.8 Hz, 3.9 Hz, 4 H, 2SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.35 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 6.88(s, 1 H, H-2), 7.12 (d, J=8.7 Hz, 1 H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4Hz, 1 H, H-4′) 8.86 (d, J=2.4 Hz, 1 H, H-6′), 10.63 (br s, 1 H, NH); MS(FAB) m/z 502 (MH⁺).

Example 7

[0727] Preparation of52-(2-ethoxy-5-(4-n-propylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-n-propylpiperazinylpiperazin-1-yl)

[0728] The titled compound was prepared as described in Example 2 byusing52-(2-ethoxy-5-(4-n-propylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-1-5-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0729] yield: 98%

[0730] mp 232.5° C. dec;

[0731] IR (neat) 3334 (NH), 1686 (C═O), 1163 (SO₂) cm⁻¹;

[0732]¹H NMR (DMSO-d₆) δ0.87 (t, J=7.5 Hz, 3 H, NCH₂CH₂CH₃), 0.93 (t,J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.36 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.56-1.72(m, 4 H, CH₂CH₂CH₃ and NCH₂CH₂CH₃), 2.58 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃),2.82(br dd, J=12.3 Hz, 11.7 Hz, 2 H, 2 SO₂NCH_(ax)), 2.94-3.07 (m, 2 H,NCH₂CH₂CH₃), 3.05-3.17 (m, 2 H, 2 SO₂NCH_(eq)), 3.47-3.58 (m, 2 H, 2⁺HNCH_(ax)), 3.79 (br d, J=11.7 Hz, 2 H, 2 ⁺HNCH_(eq)), 3.99 (s, 3 H,NCH₃), 4.24(q, J=6.9 Hz, 2 H, OCH₂CH₃), 7.25 (s, 1 H, H-2), 7.42 (d,J=9.0 Hz, 1 H, H-3′), 7.87 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 7.98 (d,J=2.4 Hz, 1 H, H-6′), 10.69 (br s, 1 H, NH⁺), 11.82(br s, 1 H, NH).

Example 8

[0733] Preparation of52-(2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is 4-isopropylpiperazinylpiperazin-1-yl)

[0734] The titled compound was prepared as described in Example 1 byusing 1-isopropylpiperazine in place of 1-methylpiperazine.

[0735] yield: 87%

[0736] mp 241.5° C. dec (CHCl₃/Et₂O);

[0737] IR (neat) 3333 (NH), 1680, 1672 (C═O), 1177 (SO₂) cm⁻¹;

[0738]¹H NMR (CDCl₃/TMS) δ0.990 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 0.993 (t,J=6.6 Hz, 6 H, CH₂(C₃)₂), 1.63 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.67-1.77(m, 2 H, CH₂CH₂CH₃), 2.60(dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.61-2.68(m, 1 H, CH(CH₃)₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.09 (dd, J=4.8Hz, 4 H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.35 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.88 (s, 1 H, H-2), 7.11 (d, J=8.7 Hz, 1 H, H-3′), 7.80 (dd,J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.86 (d, J=2.7 Hz, 1 H, H-6′), 10.62 (brs, 1 H, NH); MS (FAB) m/z 502 (MH⁺).

Example 9

[0739] Preparation of52-(2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-1-5-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-isopropylpiperazinylpiperazin-1-yl)

[0740] The titled compound was prepared as described in Example 2 byusing52-(2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0741] yield: 98%

[0742] mp 244.5° C. dec;

[0743] IR (neat) 3336(NH), 1684 (C═O), 1166 (SO₂) cm⁻¹;

[0744]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.23 (t,J=6.6 Hz, 6 H, CH(CH₃)₂), 1.37 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.57-1.72(m, 2 H, CH₂CH₂CH₃), 2.58 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.76-2.88 (m, 2H, 2 SO₂NCH_(ax)), 3.07-3.19 (m, 2 H, 2 SO₂NCH_(eq)), 3.30-3.56 (m, 3 H,CH(CH₃)₂ and 2 ⁺HNCH_(ax)), 3.82 (br d, J=12.3 Hz, 2 H, 2 ⁺HNCH_(eq)),3.99 (s, 3 H, NCH₃), 4.24 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 7.24 (s, 1 H,H-2), 7.42 (d, J=9.0 Hz, 1 H, H-3′), 7.88 (dd, J=9.0 Hz, 2.4 Hz, 1 H,H-4′), 7.99 (d, J=2.4 Hz, 1 H, H-6′), 10.38 (br s, 1 H, NH⁺) 11.78 (brs, 1 H, NH).

Example 10

[0745] Preparation of52-(2-ethoxy-5-(4-(2-fluoroethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydo-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-fluoroethyl)piperazinylpiperazin-1-yl)

[0746] The titled compound was prepared as described in Example 1 byusing 1-(2-fluoroethyl)piperazine hydrochloride in place of1-methylpiperazine.

[0747] yield: 92%

[0748] mp 204.5-205° C. (EtOAc/hexanes);

[0749] IR (neat) 3335 (NH), 1678 (C═O), 1169 (SO₂) cm⁻¹;

[0750]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.66-1.79 (m, 2 H, CH₂CH₂CH₃), 2.62-2.75 (m, 8H, NCH₂CH₂F, 2 NCH₂ and CH₂CH₂CH₃), 3.13 (dd, J=4.8 Hz, 4.5 Hz, 4 H, 2SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.35 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.49(ddd, J=47.4 Hz, 5.1 Hz, 4.5 Hz, 2 H, NCH₂CH₂F), 6.89 (s, 1 H, H-2),7.12 (d, J=8.7 Hz, 1 H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′),8.87 (d, J=2.4 Hz, 1 H, H-6′), 10.63 (br s, 1 H, NH); MS (FAB) m/z 506(MH⁺).

Example 11

[0751] Preparation of52-(2-ethoxy-5-(4-(2-fluoroethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═C₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-fluoroethyl)piperazinylpiperazin-1-yl)

[0752] The titled compound was prepared as described in Example 2 byusing52-(2-ethoxy-5-(4-(2-fluoroethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-1-5-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0753] yield: 99%

[0754] mp 76° C. dec;

[0755] IR (neat) 3333 (NH), 1684 (C═O), 1164 (SO₂) cm⁻¹;

[0756]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.36 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.58-1.70 (m, 2 H, CH₂CH₂CH₃), 2.58 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 2.74-2.91 (m, 2 H, 2 SO₂NCH_(ax)), 3.18-3.33 (m, 2H, 2 SO₂NCH_(eq)), 3.47-3.68 (m, 4 H, NCH₂CH₂F and 2 ⁺HNCH_(ax)),3.73-3.87 (m, 2 H, 2 ⁺HNCH_(eq)), 3.99 (s, 3 H, NCH₃), 4.24 (q, J=6.9Hz, 2 H, OCH₂CH₃), 4.85 (br d, J=47.1 Hz, 2 H, NCH₂CH₂F), 7.25 (s, 1 H,H-2), 7.42 (d, J=8.7 Hz, 1 H, H-3′), 7.87 (dd, J=8.7 Hz, 2.4 Hz, 1 H,H-4′), 7.98 (d, J=2.4 Hz, 1 H, H-6′), 11.14 (br s, 1 H, NH⁺), 11.87 (brs, 1 H, NH).

Example 12

[0757] Preparation of52-(5-(4-(2-fluoroethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-1-5-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-fluoroethyl)piperazinylpiperazin-1-yl)

[0758] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one and 1-(2-fluoroethyl)piperazinehydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[0759] yield: 82%

[0760] mp 158-159° C. (EtOAc/hexanes);

[0761] IR (neat) 3339 (NH), 1673 (C═O), 1168 (SO₂) cm⁻¹;

[0762]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 1.98-2.10 (m,2 H, OCH₂CH₂CH₃), 2.62-2.75 (m, 8 H, NCH₂CH₂F, 2 NCH₂ and CH₂CH₂CH₃),3.13 (dd, J=5.1 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.24(t, J=6.5 Hz, 2 H, OCH₂CH₂CH₃), 4.49 (ddd, J=47.7 Hz, 5.1 Hz, 4.5 Hz, 2H, NCH₂CH₂F), 6.89 (s, 1 H, H-2), 7.13 (d, J=9.0 Hz, 1 H, H-3′), 7.80(dd, J=9.0 Hz, 2.7 Hz, 1 H, H-4′), 8.88 (d, J=2.7 Hz, 1 H, H-6′), 10.66(br s, 1 H, NH); MS (FAB) m/z 520 (MH⁺).

Example 13

[0763] Preparation of52-(5-(4-(2-fluoroethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-fluoroethyl)piperazinylpiperazin-1-yl)

[0764] the titled compound was prepared as described in Example 2 byusing52-(5-(4-(2-fluoroethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-1-5-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0765] yield: 99%

[0766] mp 107° C. dec;

[0767] IR (neat) 3351 (NH), 1677 (C═O), 1168 (SO₂) cm⁻¹;

[0768]¹H NMR (DMSO-d6) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 0.97 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.58-1.70 (m, 2 H, CH₂CH₂CH₃), 1.70-1.80 (m,2 H, OCH₂CH₂CH₃), 2.58 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.74-2.88 (m, 2 H,2 SO₂NCH_(ax)), 3.17-3.34 (m, 2 H, 2 SO₂NCH_(eq)), 3.46-3.68 (m, 4 H,NCH₂CH₂F and 2 ⁺HNCH_(ax)), 3.73-3.87 (m, 2 H, 2 ⁺HNCH_(eq)), 3.99 (s, 3H, NCH₃), 4.15 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 4.84 (br d, J=48.0 Hz, 2H, NCH₂CH₂F), 7.24 (s, 1 H, H-2), 7.43 (d, J=8.7 Hz, 1 H, H-3′), 7.87(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 7.98 (d, J=2.4 Hz, 1 H, H-6′), 11.03(br s, 1 H, NH⁺), 11.80 (br s, 1 H, NH).

Example 14

[0769] Preparation of52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0770] The titled compound was prepared as described in Example 1 byusing 1-(3-fluoropropyl)piperazine hydrochloride in place of1-methylpiperazine.

[0771] yield: 85%

[0772] mp 217.5-218° C. (EtOAc/CHCl₃/hexanes);

[0773] IR (neat) 3333 (NH), 1676 (C═O) 1169 (SO₂) cm⁻¹;

[0774]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.69-1.89 (m, 4 H, CH₂CH₂CH₂F and CH₂CH₂CH₃),2.47 (t, J=7.5 Hz, 2 H, NCH₂CH₂), 2.54 (dd, J=4.8 Hz, 4.5 Hz, 4 H, 2NCH₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.10 (dd, J=4.8 Hz, 4.5 Hz, 4H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.35 (q, J=6.9 Hz, 2 H, OCH₂CH₃),4.43 (dt, J=46.8 Hz, 6.0 Hz, 2 H, CH₂CH₂F), 6.89 (s, 1 H, H-2), 7.13 (d,J=8.7 Hz, 1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d,J=2.4 Hz, 1 H, H-6′), 10.63 (br s, 1 H, NH); MS (FAB) m/z 520 (MH⁺).

Example 15

[0775] Preparation of52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-37-ethyl-1-5-methyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0776] A mixture of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide(270 mg, 0.52 mmol) and t-BuOK (244 mg, 2.16 mmol) in anhydrous t-BuOH(10 mL) was heated at 80° C. under nitrogen atmosphere for 5 h. Thereaction mixture was cooled to room temperature, and was evaporated todryness under vacuum. The resulting residue was diluted with water (20mL), acidified to about pH 8 with 1 N aqueous HCl solution, and wasextracted with CH₂Cl₂ (2×50 mL). Combined organic layer was dried(MgSO₄), filtered, and evaporated to dryness in vacuo to afford a whitesolid. The crude product was purified by MPLC on silica gel (3% MeOH inCHCl₃) to afford the titled compound (247 mg, 95%) as a white solid.Analytically pure compound was obtained by crystallization fromCH₂Cl₂/EtOAc/hexanes.

[0777] mp 193-194° C.;

[0778] IR (neat) 3328 (NH), 1670 (C═O), 1165 (SO₂) cm⁻¹;

[0779]¹H NMR (CDCl₃/TMS) δ1.32 (t, J=7.5 Hz, 3 H, CH₂CH₃), 1.64 (t,J=7.2 Hz, 3 H, OCH₂CH₃), 1.71-1.89 (m, 2 H, CH₂CH₂F), 2.47 (t, J=7.5 Hz,2 H, NCH₂CH₂), 2.54 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.77 (q, J=7.5Hz, 2 H, CH₂CH₃), 3.10 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 4.08 (s,3 H, NCH₃), 4.36 (q, J=7.2 Hz, 2 H, OCH₂CH₃), 4.43 (dt, J=47.1 Hz, 6.0Hz, 2 H, CH₂CH₂F), 6.90 (s, 1 H, H-2), 7.13 (d, J=9.0 Hz, 1 H, H-3′),7.80 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 8.87 (d, J=2.4 Hz, 1 H, H-6′),10.64 (br s, 1 H, NH); MS (FAB) m/z 506 (MH⁺).

Example 16

[0780] Preparation of52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-37-(3-fluoropropyl)-15-methyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₂F, R⁴═CH₂CH₃; NR⁶ R⁷ is4-(1-fluoropropyl)piperazinylpiperazin-1-yl)

[0781] The titled compound was prepared as described in Example 15 byusing4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-(3-fluoropropyl)-1-methylpyrrole-5-carboxamidein place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0782] yield: 87%

[0783] mp 225° C. dec (CH₂Cl₂/ether);

[0784] IR (neat) 3330 (NH), 1680 (C═O), 1171 (SO₂) cm⁻¹;

[0785]¹H NMR (CDCl₃/TMS) δ1.64 (t, J=7.2 Hz, 3 H, OCH₂CH₃), 1.71-1.88(m, 2 H, NCH₂CH₂CH₂F), 2.03-2.23 (m, 2 H, CH₂CH₂CH₂F), 2.47 (t, J=7.2Hz, 2 H, NCH₂CH₂), 2.54 (dd, J=5.1 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.86 (t,J=7.5 Hz, 2 H, CH₂CH₂CH₂F), 3.10 (dd, J=5.1 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂),4.09 (s, 3 H, NCH₃), 4.36 (q, J=7.2 Hz, 2 H, OCH₂CH₃), 4.41 (dt, J=47.1Hz, 6.0 Hz, 2 H, NCH₂CH₂CH₂F), 4.52 (dt, J=47.4 Hz, 6.0 Hz, 2 H,CH₂CH₂CH₂F), 6.92 (s, 1 H, H-2), 7.13 (d, J=9.0 Hz, 1 H, H-3′), 7.82(dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d, J=2.4 Hz, 1 H, H-6′), 10.67(br s, 1 H, NH); MS (FAB) m/z 538 (MH⁺).

Example 17

[0786] Preparation of37-cyclopropylmethyl-52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³=cyclopropylmethyl, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0787] The titled compound was prepared as described in Example 15 byusing3-cyclopropylmethyl-4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-1-methylpyrrole-5-carboxamidein place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0788] yield: 92%

[0789] mp 223-224.5° C. (CH₂Cl₂/EtOAc/hexanes);

[0790] IR (neat) 3328 (NH), 1685 (C═O), 1171 (SO₂) cm⁻¹;

[0791]¹H NMR (CDCl₃/TMS) δ0.27-0.32 (m, 2 H, c-C₃H₅), 0.49-0.55(m, 2 H,c-C₃H₅), 0.98-1.12(m, 1 H, c-C₃H₅), 1.64(t, J=6.9 Hz, 3 H, OCH₂CH₃),1.70-1.89(m, 2H, CH₂CH₂F), 2.47 (t, J=7.5 Hz, 2 H, NCH₂CH₂), 2.54 (dd,J=4.8 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.65 (d, J=6.9 Hz, 2 H, CHCH₂), 3.10(dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 4.10 (s, 3 H, NCH₃), 4.36 (q,J=6.9 Hz, 2 H, OCH₂CH₃), 4.43 (dt, J=47.1 Hz, 6.0 Hz, 2 H, CH₂CH₂F),7.00 (s, 1 H, H-2), 7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.80 (dd, J=8.7 Hz,2.4 Hz, 1 H, H-4′), 8.87 (d, J=2.4 Hz, 1 H, H-6′), 10.65 (br s, 1 H,NH); MS (FAB) m/z 532 (MH⁺).

Example 18

[0792] Preparation of52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-ethyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0793] The titled compound was prepared as described in Example 15 byusing4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-ethylpyrrole-5-carboxamidein place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0794] yield: 87%

[0795] mp 182-182.5° C. (CH₂Cl₂/EtOAc/ether);

[0796] IR (neat) 3334 (NH), 1681 (C═O), 1166 (SO₂) cm⁻¹;

[0797]¹H NMR (CDCl₃/TMS) δ1.33 (t, J=7.5 Hz, 3 H, CH₂CH₃), 1.48 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.65 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.71-1.89 (m,2 H, CH₂CH₂CH₂F), 2.47 (t, J=7.2 Hz, 2 H, CH₂CH₂CH₂F), 2.54 (dd, J=4.8Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.78 (q, J=7.5 Hz, 2 H, CH₂CH₃), 3.08 (dd,J=4.8 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 4.36 (q, J=6.9 Hz, 2 H, OCH₂CH₃),4.43 (dt, J=47.1 Hz, 6.0 Hz, 2 H, CH₂CH₂CH₂F), 4.46 (q, J=7.2 Hz, 2 H,NCH₂CH₃), 6.98 (s, 1 H, H-2), 7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.80 (dd,J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.89 (d, J=2.4 Hz, 1 H, H-6′), 10.67 (brs, 1 H, NH); MS (FAB) m/z 520 (MH⁺).

Example 19

[0798] Preparation of52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0799] The titled compound was prepared as described in Example 15 byusing4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-n-propylpyrrole-5-carboxamide in place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0800] yield: 95%

[0801] mp 163-164° C. (EtOAc/ether/hexanes);

[0802] IR (neat) 3332 (NH), 1671 (C═O), 1174 (SO₂) cm⁻¹;

[0803]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.02 (t,J=7.2 Hz, 3 H, CH₂NCH₂CH₃), 1.48 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.64 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.80 (m, 2 H, CH₂CH₂CH₃), 2.40 (q, J=7.2Hz, 2 H, CH₂NCH₂CH₃), 2.53 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.72 (q,J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.11 (br dd, J=5.1 Hz, 4.8 Hz, 4 H, 2SO₂NCH₂), 4.35 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.45 (q, J=7.2 Hz, 2 H,NCH₂CH₃), 6.69 (s, 1 H, H-2), 7.12 (d, J=8.7 Hz, 1 H, H-3′), 7.80 (dd,J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.88 (d, J=2.4 Hz, 1 H, H-6′), 10.65 (brs, 1 H, NH); MS (FAB) m/z 502 (MH⁺).

Example 20

[0804] Preparation of52-(2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is 4-isopropylpiperazinylpiperazin-1-yl)

[0805] The titled compound was prepared as described in Example 15 byusing4-(2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-n-propylpyrrole-5-carboxamidein place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0806] yield: 90%

[0807] mp 179.5-180° C. (CH₂Cl₂/EtOAc/hexanes);

[0808] IR (neat) 3331 (NH), 1678 (C═O), 1174 (SO₂) cm⁻¹;

[0809]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.00 (d,J=6.6 Hz, 6 H, CH(CH₃)₂), 1.48 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.64 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.80 (m, 2 H, CH₂CH₂CH₃), 2.60 (dd, J=4.8Hz, 4 H, 2 NCH₂), 2.65-2.74 (m, 1H, CH(CH₃)₂), 2.72 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 3.09 (br dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 4.35 (q,J=6.9 Hz, 2 H, OCH₂CH₃), 4.45 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 6.96 (s, 1 H,H-2), 7.11 (d, J=8.7 Hz, 1 H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1 H,H-4′), 8.88 (d, J=2.4 Hz, 1 H, H-6′), 10.65 (br s, 1 H, NH); MS (FAB)m/z 516 (MH⁺).

Example 21

[0810] Preparation of52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0811] The titled compound was prepared as described in Example 15 byusing4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-n-propylpyrrole-5-carboxamide in place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0812] yield: 93%

[0813] mp 187-188° C. (CH₂Cl₂/EtOAc/ether);

[0814] IR (neat) 3334 (NH), 1676 (C═O), 1173 (SO₂) cm⁻¹;

[0815]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.48 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.64 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.89 (m,4 H, CH₂CH₂CH₃ and CH₂CH₂CH₂F), 2.47 (t, J=7.2 Hz, 2 H, CH₂CH₂CH₂F),2.54 (dd, J=5.1 Hz, 4,8 Hz, 4 H, 2 NCH₂), 2.72 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 3.10 (br dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 4.36 (q,J=6.9 Hz, 2 H, OCH₂CH₃), 4.43 (dt, J=47.1 Hz, 6.0 Hz, 2 H, CH₂CH₂CH₂F),4.46 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 6.97 (s, 1 H, H-2), 7.13 (d, J=8.7 Hz,1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.89 (d, J=2.4 Hz, 1H, H-6′), 10.67 (br s, 1 H, NH); MS (FAB) m/z 534 (MH⁺).

Example 22

[0816] Preparation of52-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[0817] The titled compound was prepared as described in Example 15 byusing4-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-n-propylpyrrole-5-carboxamide in place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0818] yield 93%

[0819] mp 159-160.5° C. (EtOAc/ether/hexanes);

[0820] IR (neat) 3324 (NH), 1688 (C═O), 1167 (SO₂) cm⁻¹;

[0821]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.48 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.65 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.81 (m,2 H, CH₂CH₂CH₃), 2.55 (t, J=5.4 Hz, 2 H, NCH₂CH₂OH), 2.61 (dd, J=5.1 Hz,4.8 Hz, 4 H, 2 NCH₂), 2.72 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.12 (br dd,J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 3.57 (t, J=5.4 Hz, 2 H, NCH₂CH₂OH),4.37 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.46 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 6.97(s, 1 H, H-2), 7.14 (d, J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz, 2.7Hz, 1 H, H-4′), 8.89 (d, J=2.7 Hz, 1 H, H-6′), 10.67 (br s, 1 H, NH); MS(FAB) m/z 518 (MH⁺).

Example 23

[0822] Preparation of52-(2-ethoxy-5-(4-ethylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₂F, R⁴═CH₂CH₃; NR⁶ R⁷ is 4-ethylpiperazinylpiperazin-1-yl)

[0823] The titled compound was prepared as described in Example 15 byusing4-(2-ethoxy-5-(4-ethylpiperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-(3-fluoropropyl)pyrrolo-5-carboxamidein place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0824] yield: 93%

[0825] mp 161-162° C. (EtOAc/ether/hexanes);

[0826] IR (neat) 3330 (NH), 1680 (C═O) 1171 (SO₂) cm⁻¹;

[0827]¹H NMR (CDCl₃/TMS) δ1.02 (t, J=7.2 Hz, 3 H, CH₂NCH₂CH₃), 1.49 (t,J=7.2 Hz, 3 H, CHNCH₂CH₃), 1.65 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 2.06-2.22(m, 2 H, CH₂CH₂CH₂F), 2.40 (t, J=7.2 Hz, 2 H, CH₂NCH₂CH₃), 2.53 (dd,J=5.1 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.87 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₂F),3.11 (br dd, J=5.1 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 4.36 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 4.46 (q, J=7.2 Hz, 2 H, CHNCH₂CH₃), 4.52 (dt, J=47.4 Hz, 4 H,6.0 Hz, 2 H, CH₂CH₂CH₂F), 7.00 (s, 1 H, H-2), 7.12 (d, J=8.7 Hz, 1 H,H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.87 (d, J=2.4Hz, 1 H,H-6′), 10.71 (br s, 1 H, NH); MS (FAB) m/z 520 (MH⁺).

Example 24

[0828] Preparation of52-(5-(4-ethylpiperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₂F, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is 4-ethylpiperazinylpiperazin-1-yl)

[0829] The titled compound was prepared as described in Example 15 byusing4-(5-(4-ethylpiperazinylpiperazin-1-ylsulfonyl)-2-n-propoxybenzamido)-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamidein place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0830] yield: 92%

[0831] mp 137-138° C. (EtOAc/hexanes);

[0832] IR (neat) 3320 (NH), 1688 (C═O), 1168 (SO₂) cm⁻¹;

[0833]¹H NMR (CDCl₃/TMS) δ1.02 (t, J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.19 (t,J=7.2 Hz, 3 H, CH₂NCH₂CH₃), 1.49 (t, J=7.2 Hz, 3 H, CHNCH₂CH₃),1.99-2.23 (m, 4 H, CH₂CH₂CH₂F and OCH₂CH₂CH₃), 2.40 (q, J=7.2 Hz, 2 H,CH₂NCH₂CH₃), 2.53 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.87 (t, J=7.5Hz, 2 H, CH₂CH₂CH₂F), 3.11 (br dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂),4.24 (t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃), 4.46 (q, J=7.2 Hz, 2 H, CHNCH₂CH₃),4.52 (dt, J=47.1 Hz, 6.0 Hz, 2 H, CH₂CH₂CH₂F), 6.99 (s, 1 H, H-2), 7.13(d, J=8.7 Hz, 1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′) 8.88(d, J=2.4 Hz, 1 H, H-6′), 10.73 (br s, 1 H, NH); MS (FAB) m/z 552 (MH⁺).

Example 25

[0834] Preparation of52-(2-ethoxy-5(4-isopropylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-(3-fluoropropyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₂F, R⁴═CH₂CH₃; NR⁶R⁷ is 4-isopropylpiperazinylpiperazin-1-yl)

[0835] The titled compound was prepared as described in Example 15 byusing4-(2-ethoxy-5-(4-isopropylpiperazinylpiperazin-1ylsulfonyl)benzamido)-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamidein place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0836] yield: 82%

[0837] mp 182-182.5° C. (CH₂Cl₂/EtOAc/ether);

[0838] IR (neat) 3330 (NH), 1677 (C═O), 1173 (SO₂) cm⁻¹;

[0839]¹H NMR (CDCl₃/TMS) δ0.98 (d, J=6.6 Hz, 6 H, CH(CH₃)₂), 1.49 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.65 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 2.04-2.23 (m,2 H, CH₂CH₂CH₂F), 2.60 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.62-2.71(m, 1 H, CH(CH₃)₂), 2.87 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₂F), 3.09 (br dd,J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 4.35 (q, J=6.9 Hz, 2 H, OCH₂CH₃),4.45 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 4.52 (dt, J=47.4 Hz, 6.0 Hz, 2 H,CH₂CH₂CH₂F), 6.99 (s, 1 H, H-2), 7.11 (d, J=8.7 Hz, 1 H, H-3′), 7.80(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d, J=2.4 Hz 1 H, H-6′), 10.70(br s, 1 H, NH): MS (FAB) m/z 534 (MH⁺).

Example 26

[0840] Preparation of52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo-[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₂F, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0841] The titled compound was prepared as described in Example 15 byusing4(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-1-ethyl-3-(3-fluoropropyl)pyrrolo-5-carboxamidein place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0842] yield: 93%

[0843] mp 194-194.5° C. (CH₂Cl₂/EtOAc/ether);

[0844] IR (neat) 3330 (NH), 1682 (C═O), 1166 (SO₂) cm⁻¹;

[0845]¹H NMR (CDCl₃/TMS) δ1.49 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.65 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.71-1.89 (m, 2 H, NCH₂CH₂CH₂F), 2.05-2.23 (m,2 H, CH₂CH₂CH₂F), 2.47 (t, J=7.2 Hz, 2 H, NCH₂CH₂CH₂F), 2.54 (dd, J=5.1Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.87 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₂F), 3.10 (brdd, J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 4.36 (q, J=6.9 Hz, 2 H, OCH₂CH₃),4.43 (dt, J=47.4 Hz, 6.0 Hz, 2 H, NCH₂CH₂CH₂F), 4.46 (q, J=7.2 Hz, 2 H,NCH₂CH₃), 4.52 (dt, J=47.4 Hz, 6.0 Hz, 2H, CH₂CH₂CH₂F), 7.00 (s, 1 H,H-2), 7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz, 2.7 Hz, 1 H,H-4′), 8.87 (d, J=2.7 Hz, 1 H, H-6′), 10.70 (br s, 1 H, NH); MS (FAB)m/z 552 (MH⁺).

Example 27

[0846] Preparation of52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-sulfonyl)phenyl)-15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onesulfuric acid hydrogen sulfate (a compound of the formula (1) whereinR⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₂F, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0847] The titled compound was prepared as described in Example 2 byusing52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-(3-fluoropropyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74oneand 10% ethanolic H₂SO₄ solution in place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1 N HCl etheralethereal solution.

[0848] yield: 95%

[0849] mp 90.5-91° C.;

[0850] IR (neat) 3330 (NH), 1717 (C═O), 1162 (SO₂) cm⁻¹;

[0851]¹H NMR (DMSO-d₆) δ1.37 (t, J=7.1 Hz, 6 H, NCH₂CH₃ and OCH₂CH₃),1.91-2.12 (m, 4 H, CH₂CH₂CH₂F and NCH₂CH₂CH₂F), 2.55-2.67 (m, 2 H,NCH₂CH₂CH₂F), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₂F), 3.14-3.28 (m, 4 H, 2SO₂NCH₂), 3.52-3.63 (m, 2 H, 2 ⁺HNCH_(ax)), 3.75-3.86 (m, 2 H, 2^(+HNCH) _(eq)), 4.25 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.38 (q, J=7.2 Hz, 2H, NCH₂CH₃), 4.51 (dt, J=47.4 Hz, 6.0 Hz, 4 H, CH₂CH₂CH₂F andNCH₂CH₂CH₂F), 7.39 (s, 1 H, H-2 )m 7.43 (d, J=8.7 Hz, 1 H, H-3′), 7.88(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 7.97 (d, J=2.4 Hz, 1 H, H-6′), 9.22(br s, 1 H, NH), 10.86 (br s, 1 H, NH⁺).

Example 28

[0852] Preparation of52-(5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₂F, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0853] The titled compound was prepared as described in Example 15 byusing4-(5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxybenzamido)-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamidein place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0854] yield: 94%

[0855] mp 143-144° C. (EtOAc/hexanes);

[0856] IR (neat) 3318 (NH), 1687 (C═O), 1170 (SO₂) cm⁻¹;

[0857]¹H NMR (CDCl₃/TMS) δ1.20 (t, J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.49 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 1.71-1.88 (m, 2 H, NCH₂CH₂CH₂F), 1.99-2.23 (m,4 H, CH₂CH₂CH₂F and OCH₂CH₂CH₃), 2.47 (t, J=7.2 Hz, 2 H, NCH₂CH₂CH₂F),2.54 (dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.87 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₂F), 3.10 (m, 4 H, 2 SO₂NCH₂), 4.25 (t, J=6.3 Hz, 2 H,OCH₂CH₂CH₃), 4.43 (dt, J=47.1 Hz, 6.0 Hz, 2 H, NCH₂CH₂CH₂F), 4.45 (t,J=7.2 Hz, 2 H, NCH₂CH₃), 4.52 (dt, J=47.4 Hz, 6.0 Hz, 2 H, CH₂CH₂CH₂F),7.00 (s, 1 H, H-2), 7.14 (d, J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz,2.4 Hz, 1 H, H-4′), 8.88 (d, J=2.4 Hz, 1 H, H-6′), 10.74 (br s, 1 H,NH); MS (FAB) m/z 566 (MH⁺).

Example 29

[0858] Preparation of52-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-ethyl-37-(3-fluoropropyl)-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₂F, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[0859] The titled compound was prepared as described in Example 15 byusing4-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonylbenzamido)-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamidein place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0860] yield: 86%

[0861] mp 164-165° C. (EtOAc/hexanes);

[0862] IR (neat) 3526 (OH), 3322 (NH) 1694 (C═O), 1170 (SO₂) cm³¹ ¹;

[0863]¹H NMR (CDCl₃/TMS) δ1.49 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.65 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 2.06-2.23 (m, 2 H, CH₂CH₂CH₂F), 2.54 (t, J=5.4Hz, 2 H, CH₂CH₂OH), 2.61 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.87 (t,J=7.5 Hz, 2 H, CH₂CH₂CH₂F), 3.12 (br dd, J=5.1 Hz, 4.8 Hz, 4 H, 2SO₂NCH₂), 3.57 (t, J=5.4 Hz, 2 H, CH₂CH₂OH), 4.37 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 4.45 (q, J=7.2 Hz, 2 H, NCH₂CH₃) 4.53 (dt, J=47.4 Hz, 6.0 Hz,2 H, CH₂CH₂CH₂F), 7.00 (s, 1 H, H-2), 7.14 (d, J=8.7 Hz, 1 H, H-3′),7.82 (dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.88 (d, J=2.7 Hz, 1 H, H-6′),10.71 (br s, 1H, NH); MS (FAB) m/z 536 (MH⁺).

Example 30

[0864] Preparation of52-(5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl-2-n-propoxyphenyl)-15-ethyl-37-(3-fluoropropyl)1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₂F, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[0865] The titled compound was prepared as described in Example 15 byusing4-(5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxybenzamido)-1-ethyl-3-(3-fluoropropyl)pyrrole-5-carboxamidein place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)benzamido)-3-ethyl-1-methylpyrrole-5-carboxamide.

[0866] yield: 82%

[0867] mp 162-163° C. (EtOAc/hexanes);

[0868] IR (neat) 3526 (OH), 3325 (NH), 1685 (C═O), 1169 (SO₂) cm⁻¹;

[0869]¹H NMR (CDCl₃/TMS) δ1.20 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.48 (t,J=7.2 Hz, 3 H, NCH₂CH₃), 2.00-2.23 (m. 4 H, CH₂CH₂CH₃ and CH₂CH₂CH₂F),2.35 (br s, 1 H, OH), 2.55 (t, J=5.4 Hz, 2 H, CH₂CH₂OH), 2.62 (dd, J=5.1Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.87 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₂F), 3.12 (brdd, J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 3.57 (t, J=5.4 Hz, 2 H,CH₂CH₂OH), 4.26 (t, J=6.6 Hz, 2 H, CH₂CH₂CH₃), 4.46 (q, J=7.2 Hz, 2 H,NCH₂CH₃), 4.53 (dt, J=47.1 Hz, 5.7 Hz, 2 H, CH₂CH₂CH₂F), 7.00 (s, 1 H,H-2), 7.16 (d, J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz, 2.4 Hz, 1 H,H-4′) 8.89 (d, J=2.4 Hz, 1 H, H-6′), 10.75 (br s, 1 H, NH);

[0870] MS (FAB) m/z 550 (MH⁺).

Example 31

[0871] Preparation of2-(5-(4-(2-hydroxyethyl)piperazin-1ylsulfonyl)-2-n-propoxyphenyl)-5-ethyl-7-n-propyl-3,5-(dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₂CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is 4-(2-hydroxyethyl)piperazin-1-yl)

[0872] The titled compound was prepared as described in Example 15 byusing4(5-(4(2-hydroxyethylpiperazin-1-ylsulfonyl-2-n-propoxybenzamido)-1-ethyl-3-n-propylpyrrole-5-carboxamidein place of4-(2-ethoxy-5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)benzamido-3-ethyl-1-methylpyrrole-5-carboxamide.

[0873] yield: 87%

[0874] mp 159.5-160.5° C. (EtOAc/Et₂O);

[0875] IR (neat) 3519(OH), 3330 (NH), 1684 (C═O), 1164 (SO₂) cm⁻¹;

[0876]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.48 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.68-1.81(m, 2 H, CH₂CH₂CH₃), 1.99-2.11 (m, 2 H, OCH₂CH₂CH₃), 2.30 (br s, 1H,OH), 2.55 (t, J=5.4 Hz, 2 H, CH₂CH₂OH), 2.61 (dd, J=5.1 Hz, 4.5 Hz, 4 H,2 NCH₂), 2.72 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.12 (br dd, J=5.1 Hz, 4.5Hz, 4 H, 2 SO₂NCH₂), 3.57 (t, J=5.4 Hz, 2 H, CH₂CH₂OH), 4.25 (t, J=6.6Hz, 2 H, OCH₂CH₂CH₃), 4.46 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 6.97 (s, 1 H,H-2), 7.15 (d, J=8.7 Hz, 1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H,H-4′), 8.89 (d, J=2.4 Hz, 1 H, H-6′), 10.70 (br s, 1 H, NH); MS (FAB)m/z 532 (MH⁺).

Example 32

[0877] Preparation of2-(5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-onehydrogen sulfate (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₂CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazin-1-yl)

[0878] To a solution of2-(5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one(140 mg, 0.26 mmol) in anhydrous CH₂Cl₂ (7 mL) was added 10% ethanolicH₂SO₄ solution (177 μL, 0.32 mmol) at room temperature under nitrogenatmosphere, and the solution was stirred for about 20 minutes. Thereaction mixture was poured slowly into anhydrous ether (40 mL), and theresulting white precipitates were collected by filtration.

[0879] yield: 92%

[0880] mp 84.5° C. (CH₂Cl₂/Et₂O);

[0881] IR (neat) 3338 (NH), 1716 (C═O), 1173 (SO₂) cm⁻¹;

[0882]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 0.97 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.37 (t, J=7.2 Hz, 3 H, NCH₂CH₃), 1.58-1.71(m, 2 H, CH₂CH₂CH₃), 1.70-1.82 (m, 2 H, OCH₂CH₂CH₃), 2.58 (t, J=7.5 Hz,2 H, CH₂CH₂CH₃), 2.66-2.82 (m, 2 H, 2 SO₂NCH_(ax)), 3.13-3.28 (, 4 H,NCH₂CH₂ and 2 SO₂NCH_(eq)), 3.49-3.62 (m, 2 H, 2 H⁺NCH_(ax)), 3.66-3.82(m, 4 H, CH₂CH₂OH and 2 H⁺NCH_(eq)), 4.15 (t, J=6.3 Hz, 2 H,OCH₂CH₂CH₃), 4.38 (q, J=7.2 Hz, 2 H, NCH₂CH₃), 7.34 (s, 1 H, H-2), 7.44(d, J=8.7 Hz, 1 H, H-3′), 7.87 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 7.97(d, J=2.4 Hz, 1 H, H-6′), 9.32 (br s, 1 H, NH⁺).

Example 3133

[0883] Preparation of52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-yl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0884] The titled compound was prepared as described in Example 2 byusing52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0885] yield: 99%

[0886] mp 123° C. dec;

[0887] IR (neat) 3318 (NH), 1682 (C═O), 1169 (SO₂) cm⁻¹;

[0888]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.36 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.58-1.70 (m, 2 H, CH₂CH₂CH₃), 2.01-2.15 (m, 2H, CH₂CH₂CH₂F), 2.58 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.81 (br t, J=13.2Hz, 2 H, 2 SO₂NCH_(ax)), 3.08-3.24 (m, 4 H, NCH₂CH₂ and 2 SO₂NCH_(eq)),3.49-3.67 (m, 2 H, 2 ⁺HNCH_(ax)), 3.81 (br d, J=12.6 Hz, 2 H, 2⁺HNC_(eq)), 3.99 (s, 3 H, NCH₃), 4.24 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.51(dt, J=46.8 Hz, 5.7 Hz, 2 H, CH₂CH₂F), 7.25 (s, 1 H, H-2), 7.42 (d,J=9.0 Hz, 1 H, H-3′), 7.88 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 7.99 (d,J=2.4 Hz, 1 H, H-6′), 10.92 (br s, 1 H, NH⁺), 11.83 (br s, 1 H, NH).

Example 3234

[0889] Preparation of52-(2-ethoxy-5-(4-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-4,63,5-dihydro-7H4H-pyrrolo-[4,332-d]pyrimidin-74-one sulfuric acidhydrogen sulfate (a compound of theformula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃;NR⁶R⁷ is 4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0890] The titled compound was prepared as described in Example 2 byusing52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 10% ethanolic H₂SO₄ solution in place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-74H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1 N HCl etheralethereal solution.

[0891] yield: 90%

[0892] mp 82° C. dec;

[0893] IR (neat) 3314 (NH), 1717 (C═O), 1166 (SO₂) cm⁻¹;

[0894]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.36 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.58-1.70 (m, 2 H, CH₂CH₂CH₃), 1.93-2.11 (m, 2H, CH₂CH₂CH₂F), 2.58 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.56-2.74 (m, 2 H, 2SO₂NCH_(ax)) 3.15-3.30 (m, 4 H, NCH₂CH₂ and 2 SO₂NCH_(eq)), 3.53-3.65(m,2 H, 2 ⁺HNCH_(ax)), 3.75-3.88 (m, 2 H, 2 ⁺HNCH_(eq)), 4.00 (s, 3 H,NCH₃), 4.25 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.51 (dt, J=47.4 Hz, 5.6 Hz, 2H, CH₂CH₂F), 7.27 (s, 1 H, H-2), 7.44 (d, J=8.7 Hz, 1 H, H-3′), 7.89(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 7.98 (d, J=2.4 Hz, 1 H, H-6′), 9.30(br s, 1 H, NH⁺).

Example 3335

[0895] Preparation of52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onephosphonic acidhydrogen phosphate (a compound of the formula (1) whereinR⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0896] The titled compound was prepared as described in Example 2 byusing52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 10% ethanolic H₃PO₄ solution in place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1 N HCl etheralethereal solution.

[0897] yield: 91%

[0898] mp 83° C. dec;

[0899] IR (neat) 3311 (NH), 1662 (C═O), 1166 (SO₂) cm⁻¹;

[0900]¹H NMR (DMSO-d₆) δ0.92 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.35 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.57-1.70 (m, 2 H, CH₂CH₂CH₃), 1.67-1.84 (m, 2H, CH₂CH₂CH₂F), 2.41 (t, J=7.2 Hz, 2 H, NCH₂CH₂), 2.50 (br s, 4 H, 2NCH₂), 2.57 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.93 (br s, 4 H, 2 SO₂NCH₂),3.99 (s, 3 H, NCH₃), 4.22 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.41 (dt, J=47.4Hz, 5.7 Hz, 2 H, CH₂CH₂F), 7.22 (s, 1 H, H-2), 7.37 (d, J=8.7 Hz, 1 H,H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 7.88 (d, J=2.4 Hz, 1 H,H-6′), 11.72 (br s, 1 H, NH).

Example 3436

[0901] Preparation of52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onemethanesulfonic acid (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0902] The titled compound was prepared as described in Example 2 byusing52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 10% CH₃SO₃H/CH₂CH₂ solution in place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1 N HCl etheralethereal solution.

[0903] yield: 90%

[0904] mp 74° C. dec;

[0905] IR (neat) 3321 (NH), 1683 (C═O), 1173 (SO₂) cm⁻¹;

[0906]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.36 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.58-1.70 (m, 2 H, CH₂CH₂CH₃), 1.93-2.11 (m, 2H, CH₂CH₂CH₂F), 2.33 (s, 3 H, CH₃SO₃), 2.58 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 2.65 (br t, J=11.4 Hz, 2 H, 2 SO₂NCH_(ax)), 3.15-3.30 (m, 4H, NCH₂CH₂ and 2 SO₂NCH_(eq)), 3.59 (br d, J=12.9 Hz, 2 H, 2⁺HNCH_(ax)),), 3.81 (br d, J=12.9 Hz, 2 H, 2 ⁺HNCH_(eq)), 4.00 (s, 3 H,NCH₃), 4.24 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.51 (dt, J=47.4 Hz, 5.7 Hz, 2H, CH₂CH₂F), 7.26 (s, 1 H, H-2), 7.43 (d, J=8.7 Hz, 1 H, H-3′), 7.89(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 7.98 (d, J=2.4 Hz, 1 H, H-6′), 9.34(br s, 1 H, NH⁺).

Example 3537

[0907] Preparation of52-(5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0908] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-fluoropropyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-74H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[0909] yield: 90%

[0910] mp 154-154.5° C. (EtOAc/Et₂O/hexanes);

[0911] IR (neat) 3337 (NH), 1684 (C═O), 1168 (SO₂) cm⁻¹;

[0912]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.87 (m, 4 H, CH₂CH₂CH₂F andCH₂CH₂CH₃), 2.03-2.10 (m, 2 H, OCH₂CH₂CH₃), 2.47 (t, J=7.2 Hz, 2 H,NCH₂CH₂), 2.54 (dd, J=5.1 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2H, CH₂CH₂CH₃), 3.11 (br dd, J=5.1 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 4.08 (s,3 H, NCH₃), 4.24 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 4.43 (dt, J=47.1 Hz,6.0 Hz, 2 H, CH₂CH₂F), 6.89 (s, 1 H, H-2), 7.13 (d, J=8.7 Hz, 1 H,H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.88 (d, J=2.4 Hz, 1 H,H-6′), 10.66 (br s, 1 H, NH); MS (FAB) m/z 534 (MH⁺).

Example 3638

[0913] Preparation of52-(5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,43,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[0914] The titled compound was prepared as described in Example 2 byusing52-(5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0915] yield: 88%

[0916] mp 105° C. dec;

[0917] IR (neat) 3318 (NH), 1685 (C═O), 1168 (SO₂) cm⁻¹;

[0918]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 0.97 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.58-1.70 (m, 2 H, CH₂CH₂CH₃), 1.70-1.80 (m,2 H, OCH₂CH₂CH₃), 2.00-2.17 (m, 2 H, CH₂CH₂CH₂F), 2.58 (t, J=7.5 Hz, 2H, CH₂CH₂CH₃), 2.81 (br t, J=10.8 Hz, 2 H, 2 SO₂NCH_(ax)), 3.10-3.24 (m,4 H, NCH₂CH₂ and 2 SO₂NCH_(eq)), 3.56 (br d, J=12.0 Hz, 2 H, 2⁺HNCH_(ax)), 3.80 (br d, J=12.0 Hz, 2 H, 2 ⁺HNCH_(eq)) 3.99 (s, 3 H,NCH₃), 4.14 (t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃), 4.51 (dt, J=47.1 Hz, 5.7 Hz,2 H, NCH₂CH₂F), 7.24 (s, 1 H, H-2), 7.43 (d, J=9.0 Hz, 1 H, H-3′), 7.87(dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 7.9 (d, J=2.4 Hz, 1 H, H-6′), 10.85(br s, 1 H, NH⁺), 11.75 (br s, 1 H, NH).

Example 3739

[0919] Preparation of52-ethoxy-5-(4-((R)-3-fluoro-2-methylpropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-((R)-3-fluoro-2-piperazinylpiperazin-1-yl)

[0920] The titled compound was prepared as described in Example 1 byusing 1-((R)-3-fluoro-2-methylpropyl)piperazine hydrochloride in placeof 1-methylpiperazine.

[0921] yield: 90%

[0922] mp 212.5-213° C. (CHCl₃/Et₂O);

[0923] [α]_(D) ¹⁶=−5.2° (c=2.0, CHCl₃);

[0924] IR (neat) 3332 (NH), 1676 (C═O), 1169 (SO₂) cm⁻¹;

[0925]¹H NMR (CDCl₃/TMS) δ0.92 (d, J=6.6 Hz, 3 H, CHCH₃), 0.99 (t, J=7.5Hz, 3 H, CH₂CH₂CH₃), 1.64 (t, J=7.2 Hz, 3 H, OCH₂CH₃), 1.67-1.79 (m, 2H, CH₂CH₂CH₃), 1.82-2.03 (m, 1 H, CHCH₃), 2.16 (ddd, J=12.6 Hz, 6.6 Hz,1.8 Hz, 1 H, NCH₂CH), 2.33 (dd, J=12.6 Hz, 8.4 Hz, 1 H, NCH₂CH),2.45-2.58 (m, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃),3.07-3.10 (m, 4 H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.27 (ddd, J=47.4Hz, 5.4 Hz, 2.7 Hz, 2 H, CHCH₂F), 4.36 (q, J=7.2 Hz, 2 H, OCH₂CH₃), 6.89(s, 1 H, H-2), 7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.1Hz, 1 H, H-4′), 8.86 (d, J=2.1 Hz, 1 H, H-6′), 10.63 (br s, 1 H, NH); MS(FAB) m/z 534 (MH⁺).

Example 3840

[0926] Preparation of52-(2-ethoxy-5-(4-((S)-3-fluoro-2-methylpropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-((S)-3-fluoro-2-methylpropyl)piperazinylpiperazin-1-yl)

[0927] The titled compound as prepared as described in Example 1 byusing 1-((S)-3-fluoro-2-methylpropyl)piperazine hydrochloride in placeof 1-methylpiperazine.

[0928] yield: 90%

[0929] mp 212.5-213° C. (CHCl₃/Et₂O);

[0930] [α]_(D) ¹⁶=5.2° (c=2.0, CHCl₃);

[0931] IR (neat) 3332 (NH), 1676 (C═O), 1169 (SO₂) cm⁻¹;

[0932]¹H NMR (CDCl₃/TMS) δ0.92 (d, J=6.6 Hz, 3 H, CHCH₃), 0.99 (t, J=7.5Hz, 3 H, CH₂CH₂CH₃), 1.64 (t, J=7.2 Hz, 3 H, OCH₂CH₃), 1.67-1.79 (m, 2H, CH₂CH₂CH₃), 1.82-2.03 (m, 1 H CHCH₃) 2.16 (ddd, J=12.6 Hz 6.6 Hz, 1.8Hz, 1 H, NCH₂CH), 2.33 (dd, J=12.6 Hz, 8.4 Hz, 1 H, NCH₂CH), 2.45-2.58(m, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz 2 H, CH₂CH₂CH₃), 3.07-3.10 (m, 4 H,2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.27 (ddd, J=47.4 Hz, 5.4 Hz, 2.7 Hz, 2H, CHCH₂F), 4.36 (q, J=7.2 Hz, 2 H, OCH₂CH₃), 6.89 (s, 1 H, H-2), 7.13(d, J=8.7 Hz, 1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.1 Hz, 1 H, H-4′), 8.86(d, J=2.1 Hz, 1 H, H-6′), 10.63 (br s, 1 H, NH); MS (FAB) m/z 534 (MH⁺).

Example 3941

[0933] Preparation of52-(5-(4-(1,3-difluoroisopropyl)piperazinylpiperazin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(1,3-difluoroisopropyl)piperazinylpiperazin-1-yl)

[0934] The titled compound was prepared as described in Example 1 byusing 1-(1,3-difluoroisopropyl)piperazine hydrochloride in place of1-methylpiperazine.

[0935] yield: 75%

[0936] mp 218.5-219° C. (CHCl₃/EtOAc/hexanes);

[0937] IR (neat) 3338 (NH), 1676 (C═O), 1170 (SO₂) cm⁻¹;

[0938]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.67-1.80 (m, 2 H, CH₂CH₂CH₃), 2.71 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 2.82 (dd, J=5.1 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.87-3.06(m, 1 H, NCH), 3.10 (br dd, J=5.1 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 4.08 (s,3 H, NCH₃), 4.36 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.56 (dd, J=48.0 Hz, 5.1Hz, 4 H, 2 CHCH₂F), 6.89 (s, 1 H, H-2), 7.13 (d, J=9.0 Hz, 1 H, H-3′),7.80 (dd, J=9.0 Hz, 1 H, H-4′), 8.86 (d, J=2.4 Hz, 1 H, H-6′), 10.62 (brs, 1 H, NH); MS (FAB) m/z 538 (MH⁺).

Example 4042

[0939] Preparation of52-(2-ethoxy-5-(4-(4-fluorobutyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(4-fluorobutyl)piperazinylpiperazin-1-yl)

[0940] The titled compound was prepared as described in Example 1 byusing 1-(4-fluorobutyl)piperazine trifluoroacetic acid in place of1-methylpiperazine.

[0941] yield: 53%

[0942] mp 188-189° C. (EtOAc/CHCl₃/hexanes);

[0943] IR (neat) 3326 (NH), 1678 (C═O), 1167 (SO₂) cm⁻¹;

[0944]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃),1.50-1.70(m, 4 H, CH₂CH₂CH₂CH₂F), 1.64 (t, J=6.9 Hz, 3 H, OCH₂CH₃),1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 2.37(dd, J=7.5 Hz, 7.2 Hz, 2 H, NCH₂CH₂),2.53(dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 3.10 (br dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 4.08 (s, 3H, NCH₃), 4.35(q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.40 (dt, J=47.1 Hz, 6.0 Hz,2 H, CH₂CH₂F), 6.89 (s, 1 H, H-2), 7.12 (d, J=8.7 Hz, 1 H, H-3′), 7.81(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d, J=2.4 Hz, 1 H, H-6′), 10.63(br s, 1 H, NH); MS (EI) m/z 533 (M⁺).

Example 4143

[0945] Preparation of52-(5-(4-(4-fluorobutyl)piperazinylpiperazin-1ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(4-fluorobutyl)piperazinylpiperazin-1-yl)

[0946] The titled compound as prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(4-fluorobutyl)piperazine trifluoroacetic acid in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[0947] yield: 74%

[0948] mp 162-163° C. (EtOAc/Et₂O/hexanes);

[0949] IR (neat) 3335 (NH), 1683 (C═O), 1170 (SO₂) cm⁻¹;

[0950]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.18 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.50-1.94 (m, 6 H, CH₂CH₂CH₂CH₂F andCH₂CH₂CH₃), 1.98-2.09 (m, 2 H, OCH₂CH₂CH₃), 2.40 (t, J=7.2 Hz, 2 H,NCH₂CH₂), 2.56 (dd, J=5.1 Hz, 4.8 Hz 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2H, CH₂CH₂CH₃), 3.12 (br dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 4.08 (s,3 H, NCH₃), 4.24 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 4.40 (dt, J=47.4 Hz,6.0 Hz, 2 H, CH₂CH₂F), 6.89 (s, 1 H, H-2), 7.13 (d, J=8.7 Hz, 1 H,H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.85 (d, J=2.4 Hz, 1 H,H-6′), 10.69 (br s, 1 H, NH); MS (FAB) m/z 548 (MH⁺).

Example 4244

[0951] Preparation of52-(2-ethoxy-5-(4-(2,2,2-trifluoroethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2,2,2-trifluoroethyl)piperazinylpiperazin-1-yl)

[0952] The titled compound was prepared as described in Example 1 byusing 1-(2,2,2-trifluoroethyl)piperazine hydrochloride in place of1-methylpiperazine.

[0953] yield: 80%

[0954] mp 243-243.5° C. (EtOAc/hexanes);

[0955] IR (neat) 3337 (NH), 1676 (C═O), 1170 (SO₂) cm⁻¹;

[0956]¹H NMR (CDCl₃/TMS) δ0.99 (t J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64 (t,J=7.2 Hz, 3 H, OCH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 2.71 (t, J=7.5Hz, 2 H, C₂CH₂CH₃), 2.77 (dd, J=5.1 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.96 (q,J=9.6 Hz, 2 H, CH₂CF₃), 3.13 (dd, J=5.1 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂),4.08 (s, 3 H, NCH₃), 4.36 (q, J=7.2 Hz, 2 H, OCH₂CH₃), 6.89 (s, 1 H,H-2), 7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1 H,H-4′), 8.86 (d, J=2.4 Hz, 1 H, H-6′), 10.64 (br s, 1 H, NH); MS (FAB)m/z 542 (MH⁺).

Example 4345

[0957] Preparation of52-(2-n-propoxy-5-(4-(2,2,2-trifluoroethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[3,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2,2,2-trifluoroethyl)piperazinylpiperazin-1-yl)

[0958] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-ethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(2,2,2-trifluoroethyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[0959] yield: 72%

[0960] mp 189.5-190° C. (EtOAc/hexanes);

[0961] IR (neat) 3315 (NH), 1681 (C═O), 1172 (SO₂) cm³¹ ¹;

[0962]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 1.98-2.10 (m,2 H, OCH₂CH₂CH₃), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.77 (dd, J=5.1Hz, 4.8 Hz 4 H, 2 NCH₂), 2.96 (q, J=9.3 Hz, 3 H, CH₂CH₃), 3.13 (br dd,J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.25 (t, J=6.6Hz, 2 H, OCH₂CH₂CH₃), 6.89 (s, 1 H, H-2), 7.14 (d, J=8.7 Hz, 1 H, H-3′)7.80 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.87 (d, J=2.4 Hz, 1 H, H-6′),10.67 (br s, 1 H, NH) MS (FAB) m/z 556 (MH⁺).

Example 4446

[0963] Preparation of52-(2-ethoxy-5-(4-(3,3,3-trifluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3,3,3-trifluoropropyl)piperazinylpiperazin-1-yl)

[0964] The titled compound was prepared as described in Example 1 byusing 1-(3,3,3-trifluoropropyl)piperazine hydrochloride in place of1-methylpiperazine.

[0965] yield: 87%

[0966] mp 219-220° C. (EtOAc/hexanes);

[0967] IR (neat) 3339 (NH), 1684 (C═O), 1168 (SO₂) cm⁻¹;

[0968]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.64 (t,J=7.2 Hz, 3 H, OCH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 2.14-2.30 (m, 2H, CH₂CH₂CF₃), 2.56 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.60 (t, J=7.5Hz, 2 H, NCH₂CH₂CF₃), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.11 (br dd,J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.36 (q, J=7.2Hz, 2 H, OCH₂CH₃), 6.89 (s, 1 H, H-2), 7.13 (d, J=9.0 Hz, 1 H, H-3′),7.81 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d, J=2.4 Hz, 1 H, H-640 ),10.63 (br s, 1 H, NH); MS (FAB) m/z 556 (MH⁺).

Example 4547

[0969] Preparation of52-(2-n-propoxy-5-(4-(3,3,3-trifluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(3,3,3-trifluoropropyl)piperazinylpiperazin-1-yl)

[0970] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one and1-(3,3,3-trifluoropropyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[0971] yield: 81%

[0972] mp 177-178° C. (EtOAc/Et₂O);

[0973] IR (neat) 3339 (NH), 1676 (C═O), 1171 (SO₂) cm⁻¹;

[0974]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.2 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 1.98-2.10 (m,2 H, OCH₂CH₂CH₃), 2.14-2.30 (m, 2 H, CH₂CH₂CF₃), 2.56 (dd, J=5.1 Hz, 4.8Hz, 4 H, 2 NCH₂), 2.60 (t, J=7.5 Hz, 2 H, NCH₂CH₂CF₃), 2.71 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.11 (br dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂),4.08 (s, 3 H, NCH₃), 4.24 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6.89 (s, 1 H,H-2), 7.14 (d, J=8.7 Hz, 1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H,H-4′), 8.88 (d, J=2.4 Hz, 1 H, H-6′), 10.66 (br s, 1 H, NH); MS (FAB)m/z 570 (MH⁺).

Example 4648

[0975] Preparation of52-(5-(4-(2-chloroethyl)piperazinylpiperazin-1-ylsulfonyl)-2-ethoxyphenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-chloroethyl)piperazinylpiperazin-1-yl)

[0976] The titled compound was prepared as described in Example 1 byusing 1-(2-chloroethyl)piperazine hydrochloride in place of1-methylpiperazine.

[0977] yield: 87%

[0978] mp 226° C. dec (CHCl₃/Et₂O):

[0979] IR (neat) 3335 (NH), 1678 (C═O), 1172 (SO₂) cm⁻¹;

[0980]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 2.62 (dd, J=4.8Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.72 (t,J=6.6 Hz, 2 H, NCH₂CH₂Cl), 3.12 (br dd, J=4.8 Hz, 4.5 Hz, 4 H, 2SO₂NCH₂), 3.51 (t, J=6.6 Hz, 2 H, CH₂CH₂Cl), 4.08 (s, 3 H, NCH₃), 4.36(q, J=6.9 Hz, 2 H, OCH₂CH₃), 6.89 (s, 1 H, H-2), 7.13 (d, J=8.7 Hz, 1 H,H-3′), 7.80 (dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.86 (d, J=2.7 Hz, 1 H,H-6′), 10.63 (br s, 1 H, NH); MS (FAB) m/z 522 (M⁺).

Example 4749

[0981] Preparation of52-(5-(4-(3-chloropropyl)piperazinylpiperazin-1ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-chloropropyl)piperazinylpiperazin-1-yl)

[0982] The titled compound was prepared as described in Example 1 byusing 1-(3-chloropropyl)piperazine hydrochloride in place of1-methylpiperazine.

[0983] yield: 94%

[0984] mp 203° C. dec (CHCl₃/Et₂O);

[0985] IR (neat) 3333 (NH), 1679 (C═O), 1171 (SO₂) cm⁻¹;

[0986]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64(t,J=6.9 Hz, 3 H, OCH₂CH₃) 1.67-1.80 (m, 2 H, CH₂CH₂CH₃), 1.83-1.91 (m, 2H, CH₂CH₂CH₂Cl), 2.49 (t, J=6.9 Hz, 2 H, NCH₂CH₂), 2.54 (dd, J=4.8 Hz,4.2 Hz, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.10 (dr dd,J=4.8 Hz, 4.2 Hz, 4 H, 2 SO₂NCH₂), 3.52 (t, J=6.6 Hz, 2 H, CH₂CH₂Cl),4.08 (s, 3 H, NCH₃), 4.36 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 6.89 (s, 1 H,H-2), 7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H,H-4′), 8.86 (d, J=2.4 Hz, 1 H, H-6′), 10.63 (br s, 1 H, NH); MS (FAB)m/z 536 (M⁺).

Example 4850

[0987] Preparation of52-(5-(4-(3-chloropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-chloropropyl)piperazinylpiperazin-1-yl)

[0988] The titled compound was prepared as described in Example 2 byusing52-(5-(4-(3-chloropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[0989] yield: 99%

[0990] mp 135° C. dec;

[0991] IR (neat) 3338 (NH), 1682 (C═O), 1166 (SO₂) cm⁻¹;

[0992]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.36 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.58-1.70 (m, 2 H, CH₂CH₂CH₃), 2.10-2.19 (m, 2H, CH₂CH₂CH₂Cl), 2.58 (t, J=7.2 Hz, 2 H, CH₂CH₂CH₃), 2.80 (br t, J=11.4Hz, 2 H, 2 SO₂NCH_(ax)), 3.10-3.24 (m, 4 H, NCH₂CH₂ and 2 SO₂NCH_(eq)),3.54-3.59 (m, 2 H, 2 ⁺HNCH_(ax)), 3.71 (t, J=6.3 Hz, 2 H, CH₂CH₂Cl),3.77-3.82 (m, 2 H, 2 ⁺HNCH_(eq)), 3.99 (s, 3 H NCH₃), 4.24 (q, J=6.9 Hz,2 H, OCH₂CH₃), 7.25 (s, 1 H, H-2), 7.42 (d, J=8.7 Hz, 1 H, H-3′), 7.88(dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 7.99 (d, J=2.7 Hz, 1 H, H-6′), 10.83(br s, 1 H, NH⁺).

Example 4951

[0993] Preparation of52-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[0994] The titled compound was prepared as described in Example 1 byusing 1-(2-hydroxyethyl)piperazine in place of 1-methylpiperazine.

[0995] yield: 99%

[0996] mp 175° C. dec (EtOAc/hexanes);

[0997] IR (neat) 3429, 3323 (NH and OH), 1675 (C═O), 1167 (SO₂) cm⁻¹;

[0998]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64 (t,J=7.2 Hz, 3 H, OCH₂CH₃), 1.68-1.80 (m, 2 H, CH₂CH₂CH₃), 2.36 (br s, 1 H,OH), 2.55 (t, J=5.4Hz, 2 H, NCH₂CH₂), 2.61 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2NCH₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.12 (br dd, J=5.1 Hz, 4.8Hz, 4 H, 2 SO₂NCH₂), 3.58 (br t, J=5.4 Hz, 2 H, CH₂CH₂OH), 4.08 (s, 3 H,NCH₃), 4.39 (q, J=7.2 Hz, 2 H, OCH₂CH₃), 6.89 (s, 1 H, H-2), 7.14 (d,J=8.7 Hz, 1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.86 (d,J=2.7 Hz, 1 H, H-6′), 10.64 (br s, 1 H, NH); MS (FAB) m/z 504 (MH⁺).

Example 5052

[0999] Preparation of52-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂N⁶R⁷, R¹═CH₃,R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[1000] The titled compound was prepared as described in Example 2 byusing52-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1001] yield: 99%

[1002] mp 96° C. dec;

[1003] IR (neat) 3327 (NH and OH), 1679 (C═O), 1166 (SO₂) cm⁻¹;

[1004]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.36 (t,J=7.2 Hz, 3 H, OCH₂CH₃), 1.58-1.74 (m, 2 H, CH₂CH₂CH₃), 2.59 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 2.91 (br t, J=11.7 Hz, 2 H, 2 SO₂NCH_(ax)),3.10-3.27 (m, 4 H, NCH₂CH₂ and 2 SO₂NCH_(eq)), 3.58 (br d, J=11.7 Hz, 2H, 2 ⁺HNCH_(ax)), 3.68-3.82 (m, 4 H, CH₂CH₂OH and 2 ⁺HNCH_(eq)), 4.00(s, 3 H, NCH₃), 4.10 (br s, 1 H, OH), 4.23 (q, J=7.2 Hz, 2 H, OCH₂CH₃),7.26 (s, 1 H, H-2), 7.42 (d, J=9.0 Hz, 1 H, H-3′), 7.88 (dd, J=9.0 Hz,2.4 Hz, 1 H, H-4′), 8.00 (d, J=2.4 Hz, 1 H, H-6′), 10.60 (br s, 1 H,NH⁺), 11.95 (br s, 1 H, NH).

Example 5153

[1005] Preparation of52-(5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[1006] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one and 1-(2-hydroxyethyl)piperazine inplace of52(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1007] yield: 98%

[1008] mp 228° C. dec (EtOAc/hexanes):

[1009] IR (neat) 3539, 3338 (NH and OH), 1677 (C═O) 1167 (SO₂) cm⁻¹;

[1010]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.80 (m, 2 H, CH₂CH₂CH₃), 1.98-2.10 (m,2 H, OCH₂CH₂CH₃), 2.34 (br s, 1 H, OH), 2.55 (t, J=5.4 Hz, 2 H,NCH₂CH₂), 2.61 (dd, J=5.1 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2H, CH₂CH₂CH₃), 3.12 (br dd, J=5.1 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 3.57 (brs, 2 H, CH₂CH₂OH), 4.08 (s, 3 H, NCH₃), 4.25 (t, J=6.3 Hz, 2 H,OCH₂CH₂CH₃), 6.89 (s, 1 H, H-2), 7.15 (d, J=8.7 Hz, 1 H, H-3′), 7.81(dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.88 (d, J=2.7 Hz, 1 H, H-6′), 10.67(br s, 1 H, NH); MS (FAB) m/z 518 (MH⁺).

Example 5254

[1011] Preparation of52-(5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[1012] The titled compound was prepared as described in Example 2 byusing52-(5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1013] yield: 99%

[1014] mp 66.5° C. dec;

[1015] IR (neat) 3332 (NH and OH), 1676 (C═O), 1166 (SO₂) cm⁻¹;

[1016]¹H NMR (DMSO-d₆) δ0.92 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 0.96 (t,J=7.2 Hz, 3 H, OCH₂CH₂CH₃), 1.56-1.80 (m, 4 H, 2 CH₂CH₂CH₃), 2.59 (t,J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.91 (br t, J=11.7 Hz, 2 H, 2 SO₂NCH_(ax)),3.12-3.27 (m, 4 H, NCH₂CH₂ and 2 SO₂NCH_(eq)), 3.58 (dr d, J=11.7 Hz, 2H, 2 ⁺HNCH_(ax)), 3.68-3.85 (m, 4 H, CH₂CH₂OH and 2 ⁺HNCH_(eq)), 4.00(s, 3 H, NCH₃), 4.15 (t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃), 4.66 (br s, 1 H,OH), 7.28 (s, 1 H, H-2), 7.44 (d, J=9.0 Hz, 1 H, H-3′), 7.89 (dd, J=9.0Hz, 2.4 Hz, 1 H, H-4′), 8.01 (d, J=2.4 Hz, 1 H, H-6′), 10.85 (br s, 1 H,NH⁺), 12.01 (br s, 1 H, NH).

Example 5355

[1017] Preparation of52-(2-ethoxy-5-(4-(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-hydroxypropyl)piperazinylpiperazin-1-yl)

[1018] The titled compound was prepared as described in Example 1 byusing 1-(3-hydroxypropyl)piperazine in place of 1-methylpiperazine.

[1019] yield: 99%

[1020] mp 180.5° C. dec (EtOAc/hexanes);

[1021] IR (neat) 3460, 3331 (NH and OH), 1677 (C═O), 1168 (SO₂) cm⁻¹;

[1022]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.65 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.67-1.80(m, 4 H, CH₂CH₂CH₂OH and CH₂CH₂CH₃),2.58-2.65 (m, 6 H, NCH₂CH₂ and 2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 3.09 (br s, 4 H, 2 SO₂NCH₂), 3.71 (t, J=5.4 Hz, 2 H,CH₂CH₂OH), 4.08 (s, 3 H, NCH₃), 4.26 (br s, 1 H, OH), 4.37 (q, J=6.9 Hz2 H, OCH₂CH₃), 6.88 (s, 1 H, H-2), 7.13 (d, J=8.7 Hz, 1 H, H-3′) 7.77(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d, J=2.4 Hz, 1 H, H-6′), 10.65(br s, 1 H, NH); MS (FAB) m/z 518 (MH⁺).

Example 5456

[1023] Preparation of52-(2-ethoxy-5-(4-(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH2CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-hydroxypropyl)piperazinylpiperazin-1yl)

[1024] The titled compound was prepared as described in Example 2 byusing52-(2-ethoxy-5-(4-(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1025] yield: 98%

[1026] mp 81° C. dec;

[1027] IR (neat) 3333 (NH and OH), 1684 (C═O), 1163 (SO₂) cm⁻¹;

[1028]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.35 (t,J=7.2 Hz, 3 H, OCH₂CH₃), 1.58-1.76 (m, 2 H, CH₂CH₂CH₃), 1.78-1.90 (m, 2H, CH₂CH₂CH₂OH), 2.59 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2. 84 (br t, J=11.7 Hz, 2 H, 2 SO₂NCH_(ax)), 3.04-3.20 (m, 4 H, NCH₂CH₂ and 2SO₂NCH_(eq)), 3.42 (t, J=6.3 Hz, 2 H, CH₂CH₂OH), 3.52 (br d, J=11.7 Hz,2 H, 2 ⁺HNCH_(ax)), 3.80 (br d, J=11.7 Hz, 2 H, 2 ⁺HNCH_(eq)), 4.00 (s,3 H, NCH₃), 4.21 (br s, 1 H, OH), 4.23 (q, J=7.2 Hz, 2 H, OCH₂CH₃), 7.27(s, 1 H, H-2), 7.43 (d, J=9.0 Hz, 1 H, H-3′), 7.87 (dd, J=9.0 Hz, 2.4Hz, 1 H, H-4′), 8.00 (d, J=2.4 Hz, 1 H, H-6′), 11.05 (br s, 1 H, NH⁺),11.95 (br s, 1 H, NH).

Example 5557

[1029] Preparation of52-(5-(4-(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2,-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R²═CH₂CH₂CH₃; NR⁶R⁷ is4-(3-hydroxypropyl)piperazinylpiperazin-1-yl)

[1030] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-4-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one and 1-(3-hydroxypropyl)piperazinein place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1031] yield: 94%

[1032] mp 162.5° C. dec (EtOAc/hexanes);

[1033] IR (neat) 3484, 3302 (NH and OH), 1669 (C═O), 1170 (SO₂) cm⁻¹;

[1034]¹N NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.20 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.64-1.80 (m, 4 H, CH₂CH₂CH₂OH andCH₂CH₂CH₃), 1.99-2.11 (m, 2 H, OCH₂CH₂CH₃), 2.58-2.64 (m, 6 H, NCH₂CH₂and 2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.08 (br s, 4 H, 2SO₂NCH₂), 3.71 (t, J=5.4 Hz, 2 H, CH₂CH₂OH), 4.08 (s, 3 H, NCH₃), 4.26(t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃), 4.28 (br s, 1 H, OH), 6.88 (s, 1 H,H-2), 7.14 (d, J=8.7 Hz, 1 H, H-3′), 7.77 (dd, J=8.7 Hz, 2.7 Hz, 1 H,H-4′), 8.87 (d, J=2.7 Hz, 1 H, H-6′), 10.69 (br s, 1 l H, NH);

[1035] MS (FAB) m/z 532 (MH⁺).

Example 5658

[1036] Preparation of52-(5-(4-(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-4,46,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(3-hydroxypropyl)piperazinylpiperazin-1-yl)

[1037] The titled compound was prepared as described in Example 2 byusing52-(5(4-(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-74H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1038] yield: 99%

[1039] mp 62.5° C. dec;

[1040] IR (neat) 3347, 3321 (NH and OH), 1689 (C═O), 1168 (SO₂) cm⁻¹;

[1041]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 0.96(t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.57-1.87 (m, 6 H, CH₂CH₂CH₂OH and 2CH₂CH₂CH₃), 2.59 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.89 (br t, J=11.7 Hz, 2H, 2 SO₂NCH_(ax)), 3.01-3.19 (m, 4 H, NCH₂CH₂ and 2 SO₂NCH_(eq)),3.44(t, J=6.0 Hz, 2 H, CH₂CH₂OH), 3.52 (br d, J=11.7 Hz, 2 H, 2⁺HNCH_(ax)), 3.79 (br d, J=11.7 Hz, 2 H, 2 ⁺HNCH_(eq)), 4.00 (s, 3 H,NCH₃), 4.15 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 4.71 (br s, 1 H, OH), 7.29(s, 1 H, H-2), 7.44 (d, J=8.7 Hz, 1 H, H-3′), 7.89 (dd, J=8.7 Hz, 2.4Hz, 1 H, H-4′), 8.02 (d, J=2.4 Hz, 1 H, H-6′), 11.13 (br s, 1 H, NH⁺),12.05(br s, 1 H, NH).

Example 5759

[1042] Preparation of52-(2-ethoxy-5-(4-(4-hydroxybutyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-74H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(4-hydroxybutyl)piperazinylpiperazin-1-yl)

[1043] The titled compound was prepared as described in Example 1 byusing 1-(4-hydroxybutyl)piperazine in place of 1-methylpiperazine.

[1044] yield: 72%

[1045] mp 196.5° C. dec (EtOAc/hexanes);

[1046] IR (neat) 3332 (NH and OH), 1676 (C═O), 1168 (SO₂) cm⁻¹;

[1047]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.60-1.79 (m, 6 H, CH₂CH₂CH₂CH₂ and CH₂CH₂CH₃),2.41 (br s, 2 H, NCH₂CH₂), 2.60 (br t, J=4.8 Hz, 4 H, 2 NCH₂), 2.71 (t,J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.13 (br s, 4 H, 2 SO₂NCH₂), 3.49 (br s, 2 H,CH₂CH₂OH), 4.08 (s, 3 H, NCH₃), 4.36 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.78(br s, 1 H, OH), 6.88 (s, 1 H, H-2), 7.12 (d, J=8.7 Hz, 1 H, H-3′), 7.77(dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.86 (d, J=2.7 Hz, 1 H, H-6′), 10.66(br s, 1 H, NH); MS (EI) m/z 532 (MH⁺).

Example 5860

[1048] Preparation of52-(2-ethoxy-5-(4-(4-hydroxybutyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(4-hydroxybutyl)piperazinylpiperazin-1-yl)

[1049] The titled compound was prepared as described in Example 2 byusing52-(2-ethoxy-5-(4-(3-hydroxybutyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1050] yield: 98%

[1051] mp 62° C. dec;

[1052] IR (neat) 3334 (NH and OH), 1680 (C═O), 1167 (SO₂) cm⁻¹;

[1053]¹H NMR (DMSO-d₆) δ0.93 (t J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.36 (t,J=7.2 Hz, 3 H, OCH₂CH₃), 1.37-1.52 (m, 2 H, NCH₂CH₂CH₂CH₂), 1.58-1.80(m, 4 H, NCH₂CH₂CH₂CH₂ and CH₂CH₂CH₃), 2.58 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 2.84 (br t, J=11.7 Hz, 2 H, 2 SO₂NCH_(ax)), 3.00-3.18 (m, 4H, NCH₂CH₂ and 2 SO₂NCH_(eq)), 3.39 (t, J=6.3 Hz, 2 H, CH₂CH₂OH), 3.48(br d, J=11.7 Hz, 2 H, 2 ⁺HNCH_(ax)), 3.79 (br d, J=11.7 Hz, 2 H, 2⁺HNCH_(eq)), 3.99 (s, 3 H, NCH₃), 4.22 (q, J=7.2 Hz, 2 H, OCH₂CH₃), 7.26(s, 1 H, H-2), 7.42 (d, J=9.0 Hz, 1 H, H-3′), 7.84 (dd, J=9.0 Hz, 2.4Hz, 1 H, H-4′), 8.00 (d, J=2.4 Hz, 1 H, H-6′), 11.02 (br s, 1 H, NH⁺),11.84 (br s, 1 H, NH).

Example 5961

[1054] Preparation of52-(5-(4-(4-hydroxybutyl)piperazinylpiperazin-1ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(4-hydroxybutyl)piperazinylpiperazin-1-yl)

[1055] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one and 1-(4-hydroxybutyl)piperazine inplace of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1056] yield: 61%

[1057] mp 119° C. dec (EtOAc/Et₂O/hexanes);

[1058] IR (neat) 3469, 3300 (NH and OH), 1670 (C═O), 1169 (SO₂) cm⁻¹;

[1059]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.20 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.60-1.79 (m, 6 H, CH₂CH₂CH₂CH₂ andCH₂CH₂CH₃), 1.99-2.11 (m, 2 H, OCH₂CH₂CH₃), 2.41 (br s, 2 H, NCH₂CH₂),2.61 (br t, J=4.8 Hz, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃),3.13 (br s, 4 H, 2 SO₂NCH₂), 3.49 (br s, 2 H, CH₂CH₂OH), 4.08 (s, 3 H,NCH₃), 4.25 (t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃), 4.83 (br s, 1 H, OH), 6.88(s, 1 H, H-2), 7.13 (d, J=8.7 Hz, 1 H, H-3′) 7.77 (dd, J=8.7 Hz, 2.4 Hz,1 H, H-4′) 8.87 (d, J=2.4 Hz, 1 H, H-6′), 10.69 (br s, 1 H, NH); MS(FAB) m/z 546 (MH⁺).

Example 6062

[1060] Preparation of52-(5-(4-(4-hydroxybutyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onehydrochloride (a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷,R¹═CH₃, R²═H, R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(4-hydroxybutyl)piperazinylpiperazin-1-yl)

[1061] The titled compound was prepared as described in Example 2 byusing52-(5-(4-(4-hydroxybutyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1062] yield: 98%

[1063] mp 58° C. dec;

[1064] IR (neat) 3333 (NH and OH), 1679 (C═O), 1167 (SO₂) cm⁻¹;

[1065]¹H NMR (DMSO-d₆) δ0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 0.96(t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.36-1.45 (m, 2 H, NCH₂CH₂CH₂CH₂), 1.56-1.80(m, 6 H, NCH₂CH₂CH₂CH₂ and 2 CH₂CH₂CH₃), 2.59 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 2.89 (br t, J=11.7 Hz, 2 H, 2 SO₂NCH_(ax)), 3.00-3.18 (m, 4H, NCH₂CH₂ and 2 SO₂NCH_(eq)), 3.39 (t, J=6.3 Hz, 2 H, CH₂CH₂OH), 3.51(br d, J=11.4 Hz, 2 H, 2 ⁺HNCH_(ax)), 3.80 (br d, J=11.4 Hz, 2 H, 2⁺HNCH_(eq)), 4.00 (s, 3 H, NCH₃), 4.15 (t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃),4.80 (br s, 1 H, OH), 7.29 (s, 1 H, H-2), 7.44 (d, J=9.0 Hz, 1 H, H-3′)7.89 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 8.02 (d, J=2.4 Hz, 1 H, H-6′),11.14 (br s, 1 H, NH⁺), 12.12 (br s, 1 H, NH).

Example 6163

[1066] Preparation of52-(2-(2-fluoroethoxy)-5-(4-(2-fluoroethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂F; NR⁶R⁷ is4-(2-fluoroethyl)piperazinylpiperazin-1-yl)

[1067] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-(2-fluoroethoxy)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(2-fluoroethyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxypheniyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1068] yield: 95%

[1069] mp 165.5-166° C. (EtOAc/Et₂O/hexanes);

[1070] IR (neat) 3357 (NH), 1678 (C═O), 1169 (SO₂) cm⁻¹;

[1071]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.69-1.77(m, 2 H, CH₂CH₂CH₃), 2.63-2.76 (m, 6 H, NCH₂CH₂F and 2 NCH₂), 2.71 (t,J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.14 (br dd, J=4.8 Hz, 4.5 Hz, 4 H, 2SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.40-4.59 (m, 4 H, OCH₂CH₂F andNCH₂CH₂F), 4.82-5.01 (m, 2 H, OCH₂CH₂F), 6.88 (s, 1 H, H-2), 7.15 (d,J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz, 2.4 Hz 1 H, H-4′), 8.82 (d,J=2.4 Hz, 1 H, H-6′), 10.40 (br s, 1 H, NH); MS (FAB) m/z 524 (MH⁺).

Example 6264

[1072] Preparation of52-(2-(2-fluoroethoxy)-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂F; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[1073] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-(2-fluoroethoxy)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-fluoropropyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1074] yield: 95%

[1075] mp 179-180° C. (EtOAc/Et₂O/hexanes);

[1076] IR (neat) 3358 (NH), 1678 (C═O), 1171 (SO₂) cm⁻¹;

[1077]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.65-1.89(m, 4 H, CH₂CH₂CH₂F and CH₂CH₂CH₃), 2.48 (t, J=7.2 Hz, 2 H, NCH₂CH₂),2.52-2.58 (m, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃),3.06-3.15 (m, 4 H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.44 (dt, J=46.8 Hz,6.0 Hz, 2 H, NCH₂CH₂F), 4.45-4.56 (m, 2 H, OCH₂CH₂F), 4.81-5.00 (m, 2 H,OCH₂CH₂F), 6.89 (s, 1 H, H-2), 7.15 (d, J=8.7 Hz, 1 H, H-3′), 7.83 (dd,J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.81 (d, J=2.4 Hz, 1 H, H-6′), 10.39 (brs, 1 H, NH); MS (FAB) m/z 538 (MH⁺).

Example 6365

[1078] Preparation of52-(2-ethoxy-5-(4-(2-fluoroethyl)homopiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-fluoroethyl)homopiperazinylpiperazin-1-yl)

[1079] The titled compound was prepared as described in Example 1 byusing 1-(2-fluoroethyl)homopiperazine hydrochloride in place of1-methylpiperazine.

[1080] yield: 92%

[1081] mp 118-118.5° C. (EtOAc/Et₂O);

[1082] IR (neat) 3322 (NH), 1693 (C═O), 1147 (SO₂) cm⁻¹;

[1083]¹H NMR (CDCl₃/TMS) δ0.97 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.63 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.67-1.77 (m, 2 H, CH₂CH₂CH₃), 1.79-1.97 (m, 2H, NCH₂CH₂CH₂N), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.80-2.95 (m, 6 H,NCH₂CH₂F and 2 NCH₂), 3.42-3.49 (m, 4 H, 2 SO₂NCH₂), 4.08 (s, 3 H,NCH₃), 4.35 (q, J=6.9 Hz, 2 H, OCH₂CH₃) 4.49 (dt, J=47.1 Hz, 5.4 Hz, 2H, NCH₂CH₂F), 6.89 (s, 1 H, H-2), 7.10 (d, J=8.7 Hz, 1 H, H-3′) 7.85(dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.89 (d, J=2.7 Hz, 1 H, H-6′), 10.64(br s, 1 H, NH); MS (FAB) m/z 520 (MH⁺).

Example 6466

[1084] Preparation of52-(2-ethoxy-5-(4-(3-fluoropropyl)homopiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)homopiperazinylpiperazin-1-yl)

[1085] The titled compound was prepared as described in Example 1 byusing 1-(3-fluoropropyl)homopiperazine hydrochloride in place of1-methylpiperazine.

[1086] yield: 74%

[1087] mp 107-108° C. (EtOAc/Et₂O);

[1088] IR (neat) 3322 (NH), 1686 (C═O), 1148 (SO₂) cm⁻¹;

[1089]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.63(t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.72-1.79 (m, 4 H, CH₂CH₂CH₂F and CH₂CH₂CH₃),1.83-1.87 (m, 2 H, NCH₂CH₂CH₂N), 2.61 (t, J=6.9 Hz, 2 H, NCH₂CH₂),2.68-2.75 (m, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.43 (brdd, J=5.7 Hz, 5.4 Hz, 4 H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.35 (q,J=6.9 Hz, 2 H, OCH₂CH₃), 4.46 (dt, J=47.1 Hz, 5.7 Hz, 2 H, CH₂CH₂F),6.89 (s, 1 H, H-2), 7.10 (d, J=8.7 Hz, 1 H, H-3′), 7.84 (dd, J=8.7 Hz,2.4 Hz, 1 H, H-4′), 8.89 (d, J=2.4 Hz, 1 H, H-6′), 10.65 (br s, 1 H,NH); MS (FAB) m/z 534 (MH⁺)

Example 6567

[1090] Preparation of52-(2-ethoxy-5-(4-(2-(2-fluoroethoxy)ethyl)piperazinylpiperazin-1-ylsulfonylphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H, R³═

[1091]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.29 (s, 9H, 3 CH₃), 1.64 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.64-1.77 (m, 2 H,CH₂CH₂CH₃), 2.61 (br dd, J=5.4 Hz, 4.5 Hz 4 H, 2 NCH₂) 2.71 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 2.90 (s, 2 H, CH₂CO), 3.14 (br dd, J=5.4 Hz, 4.5Hz, 4 H, 2 SO₂NCH₂), 4.09 (s, 3 H, NCH₃), 4.37 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.61 (br s, 1 H, CONH), 6.89 (s, 1 H, H-2), 7.15 (d, J=8.7 Hz,1 H, H-3′), 7.83 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.87 (d, J=2.4 Hz, 1H, H-6′), 10.61 (br s, 1 H, NH); MS (FAB) m/z 573 (MH⁺).

Example 6769

[1092] Preparation of52-(5-(4-(t-butylaminocarbonylmethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(t-butylaminocarbonylmethyl)piperazinylpiperazin-1-yl)

[1093] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one and1-(t-butylaminocarbonylmethyl)piperazine trifluoroacetic acid in placeof52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1094] yield: 68%

[1095] mp 164.5-165.5° C. (EtOAc/Et₂O/hexanes);

[1096] IR (neat) 3330, 3303 (NH), 1684 (C═O), 1169 (SO₂) cm⁻¹;

[1097]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.29 (s, 9H, 3 CH₃), 1.68-1.78 (m, 2 H,CH₂CH₂CH₃), 1.98-2.08 (m, 2 H, OCH₂CH₂CH₃), 2.58-2.63 (m, 4 H, 2 NCH₂),2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.91 (s, 2 H, CH₂CO), 3.12-3.17 (m,4 H, 2 SO₂NCH₂), 4.09 (s, 3 H, NCH₃), 4.25 (t, J=6.6 Hz, 2 H,OCH₂CH₂CH₃), 6.63 (br s, 1 H, CONH), 6.90(s, 1 H, H-2), 7.16 (d, J=8.7Hz, 1 H, H-3′), 7.83 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.88 (d, J=2.4Hz, 1 H, H-6′), 10.64 (br s, 1 H, NH); MS (FAB) m/z 587 (MH⁺).

Example 6870

[1098] Preparation of52-(2-ethoxy-5-(4-(4-fluorophenyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(4-fluorophenyl)piperazinylpiperazin-1-yl)

[1099] The titled compound was prepared as described in Example 1 byusing 1-(4-fluorophenyl)piperazine in place of 1 -methylpiperazine.

[1100] yield: 95%

[1101] mp 226-227° C. (CHCl₃/Et₂O);

[1102] IR (neat) 3337 (NH), 1678 (C═O), 1169 (SO₂) cm⁻¹;

[1103]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.80 (m, 2 H, CH₂CH₂CH₃), 2.72 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.15-3.26 (m, 8 H, 4 NCH₂), 4.08 (s, 3 H, NCH₃),4.36 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 6.80-6.84 (m, 2 H, ArH-2 and 6), 6.89(s, 1 H, H-2), 6.91-6.97 (m, 2 H, ArH-3 and 5), 7.15 (d, J=8.7 Hz, 1 H,H-3′), 7.84 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.90 (d, J=2.4 Hz, 1 H,H-6′), 10.63 (br s, 1 H, NH); MS (FAB) m/z 554 (MH⁺).

Example 6971

[1104] Preparation of52-(2-ethoxy-5(4-(2-pyridyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-pyridyl)piperazinylpiperazin-1-yl)

[1105] The titled compound was prepared as described in Example 1 byusing 1-(2-pyridyl)piperazine in place of 1-methylpiperazine.

[1106] yield: 99%

[1107] mp 203-204° C. (CHCl₃/Et₂O/hexanes);

[1108] IR (neat) 3334 (NH), 1673 (C═O), 1169 (SO₂) cm⁻¹;

[1109]¹H NMR (CDCl₃/TMS) δ1.01 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.62 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.80 (m, 2 H, CH₂CH₂CH₃), 2.72 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.19 (dd, J=5.4 Hz, 5.1 Hz, 4 H, 2 NCH₂), 3.66 (dd,J=5.4 Hz, 5.1 Hz, 4 H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.34 (q, J=6.9Hz, 2 H, OCH₂CH₃), 6.58 (d, J=8.7 Hz, 1 H, PyrH-3), 6.60-6.64 (m, 1 H,PyrH-5), 6.89 (s, 1 H, H-2), 7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.45 (ddd,J=8.7 Hz, 7.2 Hz, 2.1 Hz, 1 H, PyrH-4), 7.82 (dd, J=8.7 Hz, 2.4 Hz, 1 H,H-4′), 8.12-8.15 (m, 1 H, PyrH-6), 8.88 (d, J=2.4 Hz, 1 H, H-6′), 10.62(br s, 1 H, NH); MS (FAB) m/z 537 (MH⁺).

Example 7072

[1110] Preparation of52-(2-ethoxy-5-(4-(2-pyrimidyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-pyrimidyl)piperazinylpiperazin-1-yl)

[1111] The titled compound was prepared as described in Example 1 byusing 1-(2-pyrimidyl)piperazine dihydrochloride in place of1-methylpiperazine.

[1112] yield: 94%

[1113] mp 200-201° C. (CHCl₃/Et₂O);

[1114] IR (neat) 3329 (NH), 1679 (C═O), 1169 (SO₂) cm⁻¹;

[1115]¹H NMR (CDCl₃/TMS) δ1.01 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.62 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.80 (m, 2 H, CH₂CH₂CH₃), 2.71 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.14 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 3.96 (dd,J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.34 (q, J=6.9Hz, 2 H, OCH₂CH₃), 6.48 (d, J 4.8 Hz, 1 H, PyrH-5), 6.88 (s, 1 H, H-2),7.12(d, J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′),8.25 (d, J=4.8 Hz, 2 H, PyrH-4 and H-6), 8.87 (d, J=2.4 Hz, 1 H, H-6′),10.61 (br s, 1 H, NH); MS (FAB) m/z 538 (MH⁺).

Example 7173

[1116] Preparation of1,25,6-dimethyl-52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═R²═CH₃,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is 4-methylpiperazinylpiperazin-1-yl)

[1117] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-ethoxyphenyl)-5,61,2-dimethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1118] yield: 84%

[1119] mp 232° C. dec (CHCl₃/Et₂O/hexanes);

[1120] IR (neat) 3340 (NH), 1672 (C═O ), 1172 (SO₂) cm⁻¹;

[1121]¹H NMR (CDCl₃/TMS) δ0.94 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.63(t,J=7.2 Hz, 3 H, OCH₂CH₃), 1.64-1.73(m, 2 H, CH₂CH₂CH₃), 2.28(s, 3 H,NCH₃), 2.31 (s, 3 H, CH₃), 2.51 (br dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 NCH₂),2.68 (t, J=7.5 Hz 2 H, CH₂CH₂CH₃), 3.12 (br dd, J=4.8 Hz, 4.5 Hz, 4 H, 2SO₂NCH₂), 4.04 (s, 3 H, NCH₃), 4.35 (q, J=7.2 Hz, 2 H, OCH₂CH₃), 7.11(d, J=9.0 Hz, 1 H, H-3′), 7.80 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 8.88(d, J=2.4 Hz, 1-1 H, H-6′), 10.59 (br s, 1 H, NH); MS (FAB) m/z 488(MH⁺).

Example 7274

[1122] Preparation of5,64,2-dimethyl-52-(5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl-37n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═R²═CH₃,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is 4-methylpiperazinylpiperazin-1-yl)

[1123] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-5,64,2-dimethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1124] yield: 82%

[1125] mp 199.5-200° C. (CHCl₃/Et₂O/hexanes);

[1126] IR (neat) 3311 (NH), 1677 (C═O), 1175 (SO₂) cm⁻¹;

[1127]¹H NMR (CDCl₃/TMS) δ0.94 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.18 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.61-1.73 (m, 2 H, CH₂CH₂CH₃), 1.98-2.09 (m,2 H, OCH₂CH₂CH₃), 2.26 (s, 3 H, NCH₃), 2.31 (s, 3 H, CH₃), 2.49 (dd,J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.68 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.11(br dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 4.04 (s, 3 H, NCH₃), 4.23 (t,J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 7.12 (d, J=8.7 Hz 1 H, H-3′), 7.80 (dd,J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.89 (d, J=2.4 Hz, 1 H, H-6′), 10.61 (brs, 1 H, NH); MS (FAB) m/z 502 (MH⁺).

Example 7375

[1128] Preparation of5,64,2-dimethyl-52-(2-ethoxy-5-(4-(2-fluoroethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═R²═CH₃,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃, NR⁶R⁷ is4-(2-fluoroethyl)piperazinylpiperazin-1-yl)

[1129] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-ethoxyphenyl)-5,64,2-dimethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(2-fluoroethyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-74H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1130] yield: 80%

[1131] mp 194.5° C. (CHCl₃/Et₂O/hexanes);

[1132] IR (neat) 3340 (NH), 1669 (C═O), 1169 (SO₂) cm⁻¹;

[1133]¹H NMR (CDCl₃/TMS) δ0.94 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.65-1.74 (m, 2 H, CH₂CH₂CH₃), 2.31 (s, 3 H,CH₃), 2.62-2.76 (m, 8 H, NCH₂CH₂F, 2 NCH₂ and CH₂CH₂CH₃), 3.14 (br s, 4H, 2 SO₂NCH₂), 4.04 (s, 3 H, NCH₃), 4.35 (q, J=6.9 Hz, 2 H, OCH₂CH₃),4.50 (dt, J=47.4 Hz, 4.5 Hz, 2 H, NCH₂CH₂F), 7.12 (d, J=9.0 Hz, 1 H,H-3′), 7.80 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 8.88 (d, J=2.4 Hz, 1 H,H-6′), 10.59 (br s, 1 H, NH); MS (FAB) m/z 520 (MH⁺).

Example 7476

[1134] Preparation of5,64,2-dimethyl-52-(5-(4-(2-fluoroethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═R²═CH₃,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-fluoroethyl)piperazinylpiperazin-1-yl)

[1135] The titled compound as prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-5,65,2-dimethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(2-fluoroethyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1136] yield: 69%

[1137] mp 191-192° C. (CHCl₃/Et₂O/hexanes);

[1138] IR (neat) 3308 (NH), 1681 (C═O), 1174 (SO₂) cm⁻¹;

[1139]¹H NMR (CDCl₃/TMS) δ0.94 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.61-1.73 (m, 2 H, CH₂CH₂CH₃), 1.98-2.09 (m,2 H, OCH₂CH₂CH₃), 2.31 (s, 3 H, CH₃), 2.62-2.75 (m, 8 H, NCH₂CH₂F, 2NCH₂ and CH₂CH₂CH₃), 3.11-3.15 (m, 4 H, 2 SO₂NCH₂), 4.04 (s, 3 H, NCH₃),4.24 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 4.49 (ddd, J=47.4 Hz, 4.8 Hz, 4.5Hz, 2 H, NCH₂CH₂F), 7.12 (d, J=9.0 Hz, 1 H, H-3′), 7.80 (dd, J=9.0 Hz,2.4 Hz, 1 H, H-4′), 8.89 (d, J=2.4 Hz, 1 H, H-6′), 10.61 (br s, 1 H,NH); MS (FAB) m/z 534 (MH⁺).

Example 7577

[1140] Preparation of5,64,2-dimethyl-52-(5-(2-ethoxy-4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═R²═CH₃,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[1141] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-ethoxyphenyl)-5,64,2-dimethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-fluoropropyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1142] yield: 72%

[1143] mp 214.5° C. (CHCl₃/Et₂O/hexanes):

[1144] IR (neat) 3340 (NH), 1676 (C═O) 1171 (SO₂) cm⁻¹;

[1145]¹H NMR (CDCl₃/TMS) δ0.94 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64(t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.87 (m, 4 H, CH₂CH₂CH₂F and CH₂CH₂CH₃),2.31 (s, 3 H, CH₃), 2.43-2.62 (m, 6 H, NCH₂CH₂ and 2 NCH₂), 2.68 (t,J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.11 (br s, 4 H, 2 SO₂NCH₂), 4.04(s, 3 H,NCH₃), 4.35(q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.44 (dt, J=47.4 Hz, 6.0 Hz, 2H, CH₂CH₂F), 7.12(d, J=8.7 Hz, 1 H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.87 (d, J=2.4 Hz, 1 H, H-6′), 10.59 (br s, 1 H, NH); MS (FAB)m/z 534 (MH⁺).

Example 7678

[1146] Preparation of5,64,2-dimethyl-52-(5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═R²═CH₃,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R₇ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[1147] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-5,64,3-dimethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-fluoropropyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1148] yield: 86%

[1149] mp 156-157° C. (CHCl₃/Et₂O/hexanes);

[1150] IR (neat) 3312 (NH), 1679 (C═O), 1174 (SO₂) cm⁻¹;

[1151]¹H NMR (CDCl₃/TMS) δ0.94 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19(t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.61-1.89 (m, 4 H, CH₂CH₂CH₂F andCH₂CH₂CH₃), 1.98-2.10 (m, 2 H, OCH₂CH₂CH₃), 2.31 (s, 3 H, CH₃) 2.47 (t,J=7.2 Hz, 2 H, NCH₂CH₂), 2.54 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.68(t, J=7.5 Hz, 2 Hz, CH₂CH₂CH₃), 3.11 (br dd, J=5.1 Hz, 4.8 Hz, 4 H, 2SO₂NCH₂), 4.04 (s, 3 H, NCH₃), 4.24 t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 4.43(dt, J=47.1 Hz, 6.0 Hz, 2 H, CH₂CH₂F), 7.13 (d, J=8.7 Hz, 1 H, H-3′),7.80 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.88 (d, J=2.4 Hz, 1 H, H-6′),10.61 (br s, 1 H, NH); MS (FAB) m/z 548 (MH⁺).

Example 7779

[1152] Preparation of5,64,2-dimethyl-52-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═R²═CH₃,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[1153] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-ethoxyphenyl)-5,61,2-dimethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(2-hydroxyethyl)piperazine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1154] yield: 77%

[1155] mp 130-130.5° C. (CHCl₃/Et₂O/hexanes);

[1156] IR (neat) 3555, 3323 (NH and OH), 1663 (C═O), 1168 (SO₂) cm⁻¹;

[1157]¹H NMR (CDCl₃/TMS) δ0.95 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64(t,J=6.9 Hz, 3 H, OCH₂CH₃) 1.58-1.71 (m, 2 H, CH₂CH₂CH₃), 2.31(s, 3 H,CH₃), 2.55(t, J=5.4 Hz, 2 H, NCH₂CH₂), 2.61 (dd, J=5.1 Hz, 4.5 Hz, 4 H,2 NCH₂), 2.68 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃) 3.13 (br dd, J=5.1 Hz, 4.5Hz, 4 H, 2 SO₂NCH₂), 3.57(br t, J=5.4 Hz, 2 H, CH₂CH₂OH), 4.04 (s, 3 H,NCH₃), 4.36 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 7.13 (d, J=8.7 Hz, 1 H, H-3′),7.81(dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.88 (d, J=2.7 Hz, 1 H, H-6′),10.58 (br s, 1 H, NH); MS (FAB) m/z 518 (MH⁺).

Example 7880

[1158] Preparation of5,61,2-dimethyl-52-(5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═R²═CH₃,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[1159] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-5,61,2-dimethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(2-hydroxyethyl)piperazine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4-pyrrolo-4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1160] yield: 81%

[1161] mp 202-202.5° C. (CHCl₃/Et₂O/hexanes);

[1162] IR (neat) 3402, 3313 (NH and OH), 1662 (C═O), 1173 (SO₂) cm⁻¹;

[1163]¹H NMR (CDCl₃/TMS) δ0.95 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=J 7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.60-1.73 (m, 2 H, CH₂CH₂CH₃), 1.98-2.09(m, 2 H, OCH₂CH₂CH₃), 2.31 (s, 3 H, CH₃), 2.56 (t, J=5.4 Hz, 2 H,NCH₂CH₂), 2.63 (dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.68 (t, J=7.5 Hz, 2H, CH₂CH₂CH₃), 3.14 (br dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 3.58 (t,J=5.4 Hz, 2 H, CH₂CH₂OH), 4.04 (s, 3 H, NCH₃), 4.25 (t, J=6.6 Hz, 2 H,OCH₂CH₂CH₃), 7.14 (d, J=8.7 Hz, 1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz,1 H, H-4′), 8.88 (d, J=2.4 Hz, 1 H, H-6′), 10.62 (br s, 1 H, NH); MS(FAB) m/z 532 (MH⁺).

Example 7981

[1164] Preparation of5,64,2-dimethyl-52-(2-ethoxy-5-(4-(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═R²═CH₃,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-hydroxypropyl)piperazinylpiperazin-1-yl)

[1165] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-ethoxyphenyl)-5,64,2-dimethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-hydroxypropyl)piperazine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1166] yield: 80%

[1167] mp 209-209.5° C. (CHCl₃/Et₂O/hexanes);

[1168] IR (neat) 3346, 3320 (NH and OH), 1680 (C═O), 1171 (SO₂) cm⁻¹;

[1169]¹H NMR (CDCl₃/TMS) δ0.95 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.61-1.79(m, 4 H, CH₂CH₂CH₂OH and CH₂CH₂CH₃), 1.64 (t, J=6.9 Hz, 3 H, OCH₂CH₃),2.31 (s, 3 H, CH₃), 2.65-2.83 (m, 6 H, NCH₂CH₂ and 2 NCH₂), 2.68 (t,J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.22 (br s, 4 H, 2 SO₂NCH₂), 3.73 (t, J=5.4Hz, 2 H, CH₂CH₂OH), 4.04 (s, 3 H, NCH₃), 4.36 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.76 (dd, J=8.7 Hz, 2.1 Hz, 1H, H-4′), 8.86 (d, J=2.1 Hz, 1 H, H-6′), 10.61 (br s, 1 H, NH); MS (FAB)m/z 532 (MH⁺).

Example 8082

[1170] Preparation of5,64,2-dimethyl-52-(5-(4-(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═R²═CH₃,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(3-hydroxypropyl)piperazinylpiperazin-1-yl)

[1171] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-5,64,2-dimethyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-hydroxypropyl)piperazine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1172] yield: 54%

[1173] mp 182-183° C. (CHCl₃/Et₂O/hexanes);

[1174] IR (neat) 3490, 3310 (NH and OH), 1672 (C═O), 1172 (SO₂) cm⁻¹;

[1175]¹H NMR (CDCl₃/TMS) δ0.95 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.20 (t,J=7.2 Hz, 3 H, OCH₂CH₂CH₃), 1.61-1.76(m, 4 H, CH₂CH₂CH₂OH andCH₂CH₂CH₃), 1.99-2.10 (m, 2 H, OCH₂CH₂CH₃), 2.31 (s, 3 H, CH₃),2.62-2.67 (m, 6 H, NCH₂CH₂ and 2 NCH₂), 2.69 (t, J=7.2 Hz, 2 H,CH₂CH₂CH₃), 3.07-3.13 (m, 4 H, 2 SO₂NCH₂), 3.71 (t, =5.4 Hz, 2 H,CH₂CH₂OH), 4.04 (s, 3 H, NCH₃), 4.25 (t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃),7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.77 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′),8.87 (d, J=2.4 Hz, 1 H, H-6′), 10.65 (br s, 1 H, NH); MS (FAB) m/z 546(MH⁺).

Example 8183

[1176] Preparation of26-chloro-52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═Cl,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is 4-methylpiperazinylpiperazin-1-yl)

[1177] The titled compound was prepared as described in Example 1 byusing26-chloro-52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-4,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1178] yield: 97%

[1179] mp 115-116° C. (EtOAc/CHCl₃/hexanes;

[1180] IR (neat) 3326 (NH), 1680 (C═O), 1168 (SO₂) cm⁻¹;

[1181]¹H NMR (CDCl₃/TMS) δ0.96 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.68-1.79 (m, 2 H, CH₂CH₂CH₃), 2.28 (s, 3 H,NCH₃), 2.49-2.52 (m, 4 H, 2 NCH₂), 2.72 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃),3.11-3.13 (m, 4 H, 2 SO₂NCH₂), 4.07 (s, 3 H, NCH₃), 4.36 (q, J=6.9 Hz, 2H, OCH₂CH₃), 7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz, 2.4 Hz,1 H, H-4′), 8.85 (d, J=2.4 Hz, 1 H, H-6′), 10.72 (br s, 1 H, NH); MS(FAB) m/z 508 (MH⁺).

Example 8284

[1182] Preparation of26-chloro-2-(5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═Cl,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is 4-methylpiperazinylpiperazin-1-yl)

[1183] The titled compound was prepared as described in Example 1 byusing26-chloro-52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1184] yield: 97%

[1185] mp 194-194.5° C. (EtOAc/CHCl₃/hexanes);

[1186] IR (neat) 3306 (NH), 1686 (C═O), 1175 (SO₂) cm⁻¹;

[1187]¹H NMR (CDCl₃/TMS) δ0.96 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 1.99-2.10 (m,2 H, OCH₂CH₂CH₃), 2.27 (s, 3 H, NCH₃), 2.49 (dd, J=5.1 Hz, 4.5 Hz, 4 Hz,2 NCH₂), 2.72 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.11 (br dd, J=5.1 Hz, 4.5Hz, 4 H, 2 SO₂NCH), 4.07 (s, 3 H, NCH₃) 4.25 (t, J=6.6 Hz, 2 H,OCH₂CH₂CH₃), 7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz, 2.4 Hz,1 H, H-4′), 8.87 (d, J=2.4 Hz, 1 H, H-6′), 10.74 (br s, 1 H, NH): MS(FAB) m/z 522 (MH⁺).

Example 8385

[1188] Preparation of26-chloro-52-(2-ethoxy-5-(4-(2-fluoroethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═Cl,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-fluoroethyl)piperazinylpiperazin-1-yl)

[1189] The titled compound was prepared as described in Example 1 byusing26-chloro-52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(2-fluoroethyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1 -methylpiperazine.

[1190] yield: 96%

[1191] mp 222-223° C. (EtOAc/CHCl₃/hexanes);

[1192] IR (neat) 3330 (NH), 1674 (C═O), 1168 (SO₂) cm⁻¹;

[1193]¹H NMR (CDCl₃/TMS) δ0.96 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.65 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 2.62-2.75 (m, 6H, NCH₂CH₂F and 2 NCH₂), 2.72 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.11-3.14(m, 4 H, 2 SO₂NCH₂), 4.08 (s, 3 H, NCH₃), 4.37 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 4.50 (td, J=47.4 Hz, 4.5 Hz, 2 H, NCH₂CH₂F), 7.13 (d, J=8.7Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d, J=2.4Hz, 1 H, H-6′), 10.70 (br s, 1 H, NH); MS (FAB) m/z 540 (MH⁺).

Example 8486

[1194] Preparation of26-chloro-52-(5-(4-(2-fluoroethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═Cl,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-fluoroethyl)piperazinylpiperazin-1-yl)

[1195] The titled compound was prepared as described in Example 1 byusing26-chloro-52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(2-fluoroethyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-74H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1196] yield: 97%

[1197] mp 184-184.5° C. (EtOAc/CHCl₃/hexanes);

[1198] IR (neat) 3313 (NH), 1687 (C═O), 1173 (SO₂) cm⁻¹;

[1199]¹H NMR (CDCl₃/TMS) δ0.96 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 1.99-2.10 (m,2 H, OCH₂CH₂CH₃), 2.62-2.75 (m, 8 H, NCH₂CH₂F, 2 NCH₂ and CH₂CH₂CH₃),3.10-3.15 (m, 4 H, 2 SO₂NCH₂), 4.07 (s, 3 H, NCH₃), 4.25 (t, J=6.6 Hz, 2H, OCH₂CH₂CH₃), 4.49 (ddd, J=47.7 Hz, 5.1 Hz, 4.5 Hz, 2 H, NCH₂CH₂F),7.14 (d, J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′),8.87 (d, J=2.4 Hz, 1 H, H-6′), 10.74 (br s, 1 H, NH); MS (FAB) m/z 554(MH⁺).

Example 8587

[1200] Preparation of26-chloro-52-(2-ethoxy-5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═Cl,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[1201] The titled compound as prepared as described in Example 1 byusing26)-chloro-52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-fluoropropyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1202] yield: 94%

[1203] mp 181-182° C. (CHCl₃/hexanes);

[1204] IR (neat) 3336 (NH), 1681 (C═O), 1170 (SO₂) cm⁻¹;

[1205]¹H NMR (CDCl₃/TMS) δ0.96 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.64(t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.73-1.84 (m, 4 H, CH₂CH₂CH₂F and CH₂CH₂CH₃),2.47 (t, J=7.2 Hz, 2 H, NCH₂CH₂), 2.54 (dd, J=5.4 Hz, 4.2 Hz, 4 H, 2NCH₂), 2.72 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.10(br dd, J=5.4 Hz, 4.2 Hz,4 H, 2 SO₂NCH₂), 4.08(s, 3 H, NCH₃), 4.37 (q, J=6.9 Hz, 2 H, OCH₂CH₃),4.43 (dt, J=47.4 Hz, 6.0 Hz, 2 H, CH₂CH₂F), 7.13 (d, J=8.7 Hz, 1 H,H-3′), 7.82(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d, J=2.4 Hz, 1 H,H-6′), 10.71 (br s, 1 H, NH); MS (FAB) m/z 554 (MH⁺).

Example 8688

[1206] Preparation of26-chloro-52-(5-(4-(3-fluoropropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═Cl,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[1207] The titled compound was prepared as described in Example 1 byusing26-chloro-52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-fluoropropyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1208] yield: 79%

[1209] mp 179-180° C. (EtOAc/CHCl₃/hexanes);

[1210] IR (neat) 3315 (NH), 1690 (C═O), 1172 (SO₂) cm⁻¹;

[1211]¹H NMR (CDCl₃/TMS) δ0.96 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.89 (m, 4 H, CH₂CH₂CH₂F andCH₂CH₂CH₃), 1.99-2.10 (m, 2 H, OCH_(l CH) ₂CH₃), 2.47 (t, J=7.2 Hz, 2 H,NCH₂CH₂), 2.54 (dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.72 (t, J=7.5 Hz, 2H, CH₂CH₂CH₃), 3.10 (br dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 4.07 (s,3 H, NCH₃), 4.25 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 4.43 (dt, J=47.1 Hz,6.0 Hz, 2 H, CH₂CH₂F), 7.14 (d, J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7Hz, 2.4 Hz, 1 H, H-4′), 8.87 (d, J=2.4 Hz, 1 H, H-6′), 10.75 (br s, 1 H,NH); MS (FAB) m/z 568 (MH⁺).

Example 8789

[1212] Preparation of26-chloro-52-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═Cl,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[1213] The titled compound was prepared as described in Example 1 byusing26-chloro-52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(2-hydroxyethyl)piperazine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1214] yield 96%

[1215] mp 201-201.5° C. (CHCl₃/hexanes);

[1216] IR (neat) 3553, 3327 (NH and OH), 1677 (C═O); 1168 (SO₂) cm⁻¹;

[1217]¹H NMR (CDCl₃/TMS) δ0.96 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.65 (t,J=6.9 Hz, 3H, OCH₂CH₃), 1.67-1.77 (m, 2 H, CH₂CH₂CH₃), 2.57 (t, J=5.4Hz, 2 H, NCH₂CH₂), 2.64 (dd, J=4.5 Hz, 4 H, 2 NCH₂), 2.72 (t, J=7.5 Hz,2 H, CH₂CH₂CH₃), 3.14 (br dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 3.59(t, J=5.4 Hz, 2 H, CH₂CH₂OH), 4.07 (s, 3 H, NCH₃), 4.37 (q, J=6.9 Hz, 2H, OCH₂CH₃), 7.15 (d, J=8.7 Hz, 1 H, H-3′), 7.82 (dd, J=8.7 Hz, 2.7 Hz,1 H, H-4′), 8.86 (d, J=2.7 Hz, 1 H, H-6′), 10.71 (br s, 1 H, NH); MS(FAB) m/z 538 (MH⁺).

Example 8890

[1218] Preparation of26-chloro-52-(5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═Cl,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[1219] The titled compound was prepared as described in Example 1 byusing26-chloro-52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(2-hydroxyethyl)piperazine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1220] yield: 94%

[1221] mp 194-195° C. (EtOAc/CHCl₃/hexanes);

[1222] IR (neat) 3452, 3318 (NH and OH), 1687 (C═O), 1173 (SO₂) cm⁻¹;

[1223]¹H NMR (CDCl₃/TMS) δ0.96 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.79 (m, 2 H, CH₂CH₂CH₃), 1.99-2.11 (m,2 H, OCH₂CH₂CH₃), 2.32 (br s, 1 H, OH), 2.55 (dd, J=5.4 Hz, 5.1 Hz, 2 H,NCH₂CH₂), 2.61 (dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 NCH₂), 2.72 (t, J=7.5 Hz, 2H, CH₂CH₂CH₃), 3.12 (br dd, J=5.1 Hz, 4.8 Hz, 4 H, 2 SO₂NCH₂), 3.57-3.58(m, 2 H, CH₂CH₂OH), 4.07 (s, 3 H, NCH₃), 4.26. (t, J=6.6 Hz, 2 H,OCH₂CH₂CH₃), 7.5 Hz, (d, J=8.7 Hz, 1 H, H-3′), 7.83 (dd, J=8.7 Hz, 2.4Hz, 1 H, H-4′), 8.87 (d, J=2.4 Hz, 1 H, H-6′), 10.75 (br s, 1 H, NH); MS(FAB) m/z 552 (MH⁺).

Example 8991

[1224] Preparation of26-chloro-52-(2-ethoxy-5-(4-(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one (acompound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═Cl,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-hydroxypropyl)piperazinylpiperazin-1-yl)

[1225] The titled compound was prepared as described in Example 1 byusing26-chloro-52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-hydroxypropyl)piperazine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1226] yield: 98%

[1227] mp 189-189.5° C. (CHCl₃/hexanes);

[1228] IR (neat) 3331 (NH and OH), 1686 (C═O), 1168 (SO₂) cm⁻¹;

[1229]¹H NMR (CDCl₃/TMS) δ0.96 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.65 (t,J=6.9 Hz, 3H, OCH₂CH₃), 1.67-1.79 (m, 4 H , CH₂CH₂CH₂OH and CH₂CH₂CH₃),2.64 (br s, 6 H, NCH₂CH₂ and 2 NCH), 2.72 (t, J=7.2 Hz, 2 H, CH₂CH₂CH₃),3.10 (br s, 4 H, 2 SO₂NCH₂), 3.72 (t, J=5.4 Hz, 2 H, CH₂CH₂OH), 4.08 (s,3 H, NCH₃), 4.38 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 7.14 (d, J=8.7 Hz, 1 H,H-3′), 7.79 (dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 8.85 (d, J=2.7 Hz, 1 H,H-6′), 10.73 (br s, 1 H, NH); MS (FAB) m/z 552 (MH⁺).

Example 9092

[1230] Preparation of26-chloro-52-(5-(4-(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═Cl,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(3hydroxypropyl)piperazinylpiperazin-1-yl)

[1231] The titled compound was prepared as described in Example 1 byusing26-chloro-52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-hydroxypropyl)piperazine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1232] yield: 89%

[1233] mp 192-193° C. (EtOAc/CHCl₃/hexanes;

[1234] IR (neat) 3419, 3313 (NH and OH), 1688 (C═O), 1173 (SO₂) cm⁻¹;

[1235]¹H NMR (CDCl₃/TMS) δ0.97 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.20 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.64-1.79 (m, 4 H, CH₂CH₂OH and CH₂CH₂CH₃),2.00-2.11 (m, 2 H, OCH₂CH₂CH₃), 2.59-2.62 (m, 6 H, NCH₂CH₂ and 2 NCH₂),2.72 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.04-3.12 (m, 4 H, 2 SO₂NCH₂), 3.71(t, J=5.4 Hz, 2 H, CH₂CH₂OH), 4.08 (s, 3 H, NCH₃), 4.27 (t, J=6.6 Hz, 2H, OCH₂CH₂CH₃), 7.14 (d, J=9.0 Hz, 1 H, H-3′), 7.79 (dd, J=9.0 Hz, 2.4Hz, 1 H, H-4′), 8.86 (d, J=2.4 Hz, 1 H, H-6′), 10.77 (br s, 1 H, NH); MS(FAB) m/z 566 (MH⁺).

Example 9193

[1236] Preparation of26-bromo-52-(2-ethoxy-5-(4-methylpiperazinylpiperazin-1-ylsulfonyl)phenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═Br,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is 4-methylpiperazinylpiperazin-1-yl)

[1237] The titled compound was prepared as described in Example 1 byusing26-bromo-52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[e(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═I, R³ 50CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(3-fluoropropyl)piperazinylpiperazin-1-yl)

[1238] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-26-iodo-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-fluoropropyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33-d]pyrimidin-74-oneand 1-(3-fluoropropyl)piperazine hydrochloride in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,3-d]pyrimidin-74-oneand 1-methylpiperazine.

[1239] yield 89%

[1240] mp 204-204.5° C. (EtOAc/CHCl₃/hexanes;

[1241] IR (neat) 3310 (NH), 1685 (C═O), 1171 (SO₂) cm⁻¹;

[1242]¹H NMR (CDCl₃/TMS) δ0.97 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.65-1.89 (m, 4 H, CH₂CH₂CH₂F andCH₂CH₂CH₃), 1.98-2.10 (m, 2 H, OCH₂CH_(CH) ₃), 2.47 (t, J=7.2 Hz, 2 H,NCH₂CH₂), 2.54 (dd, J=5.4 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2H, CH₂CH₂CH₃), 3.10 (br dd, J=5.4 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 4.11 (s,3 H, NCH₃), 4.25 (t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃), 4.43 (dt, J=47.1 Hz,6.0 Hz, 2 H, CH₂CH₂F), 7.14 (d, J=9.0 Hz, 1 H, H-3′), 7.82 (dd, J=9.0Hz, 2.7 Hz, 1 H, H-4′), 8.87 (d, J=2.7 Hz, 1 H, H-6′), 10.70 (br s, 1 H,NH); MS (FAB) m/z 660 (MH⁺).

Example 107109

[1243] Preparation of52-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-26-iodo-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═I,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[1244] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-ethoxyphenyl)-26-iodo-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(2-hydroxyethyl)piperazine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1245] yield 99%

[1246] mp 194-195° C. (CHCl₃/hexanes;

[1247] IR (neat) 3442, 3323 (NH and OH), 1677 (C═O), 1171 (SO₂) cm⁻¹;

[1248]¹H NMR (CDCl₃/TMS) δ0.97 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.65 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.66-1.78 (m, 2 H, CH₂CH₂CH₃), 2.56 (t, J=5.4Hz, 2 H, NCH₂CH₂), 2.62 (dd, J=4.8 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.71 (t,J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.12 (br dd, J=4.8 Hz, 4.5 Hz, 4 H, 2SO₂NCH₂), 3.58 (t, J=5.4 Hz, 2 H, CH₂CH₂OH), 4.11 (s, 3 H, NCH₃), 4.37(q, J=6.9 Hz, 2 H, OCH₂CH₃), 7.15 (d, J=8.7 Hz, 1 H, H-3′), 7.82 (dd,J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d, J=2.4 Hz, 1 H, H-6′), 10.68 (brs, 1 H, NH); MS (FAB) m/z 630 (MH⁺).

Example 108110

[1249] Preparation of52-(5-(4-(2-hydroxyethyl)piperazinylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-26-iodo-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═I,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-hydroxyethyl)piperazinylpiperazin-1-yl)

[1250] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-26-iodo-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(2-hydroxyethyl)piperazine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1251] yield 97%

[1252] mp 183-184° C. (EtOAc/CHCl₃/hexanes;

[1253] IR (neat) 3305 (NH and OH), 1686 (C═O), 1172 (SO₂) cm⁻¹;

[1254]¹H NMR (CDCl₃/TMS) δ0.97 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.66-1.78 (m, 2 H, CH₂CH₂CH₃), 1.99-2.11 (m,2 H, OCH₂CH₂CH₃), 2.31 (br s, 1 H, OH), 2.55 (t, J=5.4 Hz, 2 H,NCH₂CH₂), 2.61 (dd, J=5.4 Hz, 4.5 Hz, 4 H, 2 NCH₂), 2.71 (t, J=7.5 Hz, 2H, CH₂CH₂CH₃), 3.12 (br dd, J=5.4 Hz, 4.5 Hz, 4 H, 2 SO₂NCH₂), 3.57 (brt, J=5.4 Hz, 2 H, CH₂CH₂OH), 4.11 (s, 3 H, NCH₃), 4.26 (t, J=6.6 Hz, 2H, OCH₂CH₂CH₃), 7.15 (d, J=8.7 Hz, 1 H, H-3′), 7.83 (dd, J=8.7 Hz, 2.4Hz, 1 H, H-4′), 8.87 (d, J=2.4 Hz, 1 H, H-6′), 10.71 (br s, 1 H, NH); MS(FAB) m/z 644 (MH⁺).

Example 109111

[1255] Preparation of52-(2-ethoxy-5-(4-(3-hydroxypropyl)piperazinylpiperazin-1-ylsulfonyl)phenyl)-26-iodo-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═I,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-hydroxypropyl)piperazinylpiperazin-1-yl)

[1256] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-ethoxyphenyl)-26-iodo-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-hydroxypropyl)piperazine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1257] yield 96%

[1258] mp 120-121° C. (CHCl₃/hexanes;

[1259] IR (neat) 3341 (NH and OH), 1678 (C═O), 1172 (SO₂) cm⁻¹;

[1260]¹H NMR (CDCl₃/TMS) δ0.97 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.53-1.64(m, 2 H, CH₂CH₂CH₂OH), 1.63-1.76 (m, 2 H, CH₂CH₂CH₃), 1.65 (t, J=6.9 Hz,3 H, OCH₂CH₃), 2.62-2.74 (m, 6 H, NCH₂CH₂ and 2 NCH₂), 2.71 (t, J=7.2Hz, 2 H, CH₂CH₂CH₃), 3.07-3.15 (m, 4 H, 2 SO₂NCH₂), 3.71 (t, J=5.1 Hz, 2H, CH₂CH₂OH), 4.11 (s, 3 H, NCH₃), 4.38 (q, J=6.9 Hz, 2 H, OCH₂CH₃),7.13 (d, J=8.7 Hz, 1 H, H-3′), 7.79 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′),8.85 (d, J=2.4 Hz, 1 H, H-6′), 10.68 (br s, 1 H, NH); MS (FAB) m/z 644(MH⁺).

Example 110112

[1261] Preparation of52-(5-(4-(3-hydroxypropyl)piperazinylpiperazin-1ylsulfonyl)-2-n-propoxyphenyl)-26-iodo-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═I,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(3-hydroxypropyl)piperazinylpiperazin-1-yl)

[1262] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-26-iodo-15-methyl-37-n-propyl-1.63.5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(3-hydroxypropyl)piperazine in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1263] yield 89%

[1264] mp 206-206.5° C. (EtOAc/CHCl₃/hexanes);

[1265] IR (neat) 3423, 3310 (NH and OH), 1683 (C═O), 1171 (SO₂) cm⁻¹;

[1266]¹H NMR (CDCl₃/TMS) δ0.97 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.20(t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.62-1.78 (m, 4 H, CH₂CH₂CH₂OH andCH₂CH₂CH₃), 1.99-2.11 (m, 2 H, OCH₂CH₂CH₃), 2.58-2.63 (m, 6 H, NCH₂CH₂and 2 NCH₂), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.03-3.12 (m, 4 H, 2SO₂NCH₂), 3.71 (t, J=5.4 Hz, 2 H, CH₂CH₂OH), 4.11 (s, 3 H, NCH₃), 4.26(t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 7.14 (d, J=9.0 Hz, 1 H, H-3′), 7.79 (dd,J=9.0 Hz, 2.4 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d, J=2.4 Hz, 1 H, H-6′),10.72 (br s, 1 H, NH); MS (FAB) m/z 658 (MH⁺).

Example 111113

[1267] Preparation of52-(5-(4-(2-aminoethyl)piperidinylpiperidin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-aminoethyl)piperidinylpiperidin-1-yl)

[1268] A mixture of52-(5-(4-cyanomethyl)piperidinylpiperidin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(217 mg, 0.44 mmol) and Raney Ni (1.5 g wet; washed with H₂O and EtOH)in glacial acetic acid (20 mL) was purged with H₂ three times, and wasvigorously stirred under hydrogen atmosphere (1 atm; a balloon) at roomtemperature for 22 h. The reaction mixture was filtered through a Celitepad, washed well with 10% MeOH in CHCl₃ (20 mL), and the filtrate wasevaporated to dryness under vacuum to give a green oil. The resultingresidue was purified by MPLC on silica gel (gradient elution: 10% MeOHin CHCl₃ followed by 10% 2 N ammonia methanolic solution in CHCl₃) toafford the titled compound (185 mg, 84%) as a yellow oil. Analyticallypure compound was obtained by crystallization from EtOH/Et₂O.

[1269] mp 60° C.

[1270] IR (neat) 3335 (NH), 1685 (C═O), 1165 (SO₂) cm⁻¹;

[1271]¹H NMR (DMSO-d₆) δ0.92 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.07-1.35(m, 5 H, CHCH₂ and 2 CH_(ax)), 1.35 (t, J=6.9 Hz, 3 H, OCH₂CH₃),1.57-1.70 (m, 4 H, CH₂CH₂CH₃ and 2 CH_(eq)), 2.23 (br t, J=11.4 Hz, 2 H,2 NCH_(ax)), 2.48-2.59 (m, 4 H, CH₂CH₂CH₂ and CH₂CH₂CH₃), 3.61 (br d,J=11.4 Hz, 2 H, 2 NCH_(eq)), 3.98 (s, 3 H, NCH₃), 4.22 (q, J=6.9 Hz, 2H, OCH₂CH₃), 7.22 (s, 1 H, H-2), 7.35 (d, J=8.7 Hz, 1 H, H-3′), 7.80(dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 7.91 (d, J=2.7 Hz, 1 H, H-6′); MS(FAB) m/z 502 (MH⁺).

Example 112114

[1272] Preparation of52-(5-(4-(2-aminoethyl)piperidinylpiperidin-1-ylsulflonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-aminoethyl)piperidinylpiperidin-1-yl)

[1273] The titled compound was prepared as described in Example 111113by using52-(5-(4-(cyanomethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(5-(4-(cyanomethyl)piperidinylpiperidin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-74H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1274] yield: 90%

[1275] mp 145° C. dec (EtOH/Et₂O);

[1276] IR (neat) 3304 (NH), 1673 (C═O), 1152 (SO₂) cm⁻¹;

[1277]¹H NMR (DMSO-d₆) δ0.92 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 0.97(t,J=7.2 Hz, 3 H, OCH₂CH₂CH₃), 1.12-1.28 (m, 3 H, CHCH₂), 1.60-1.79 (m, 8H, 2 CH₂CH₂CH₃ and 2 CH₂), 2.17-2.28 (m, 2 H, 2 NCH_(ax)), 2.44-2.53 (m,2 H, CH₂CH₂NH₂), 2.57 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃)), 3.63 (br d, J=10.5Hz, 2 H, 2 NCH_(eq)), 3.99 (s, 3 H, NCH₃), 4.13 (t, J=6.0 Hz, 2 H,OCH₂CH₂CH₃), 7.22 (s, 1 H, H-2), 7.37 (d, J=8.7 Hz, 1 H, H-3′), 7.80(dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 7.92 (d, J=2.4 Hz, 1 H, H-6′); Ms(FAB) m/z 516 (MH⁺).

Example 113115

[1278] Preparation of52-(5-(4-(3-aminopropyl)piperidinylpiperidin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(3-aminopropyl)piperidinylpiperidin-1-yl)

[1279] The titled compound was prepared as described in Example 111113by using52-(5-(4-(2-cyanoethyl)piperidinylpiperidin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo-[4,33,2-d]pyrimidin-74-onein place of52-(5-(4-(cyanomethyl)piperidinylpiperidin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1280] yield: 87%

[1281] mp 55° C. dec (THF/Et₂O);

[1282] IR (neat) 3338 (NH), 1683 (C═O), 1162 (SO₂) cm⁻¹;

[1283]¹H NMR (DMSO-d₆) δ0.92 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.08-1.20(m, 5 H, CHCH₂ and 2CH_(ax)), 1.27-1.41 (m, 2 H, CH₂CH₂CH₂NH₂), 1.35 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.57-1.70 (m, 4 H, CH₂CH₂CH₃ and 2 CH_(eq)),2.16-2.29 (m, 2 H, 2 NCH_(ax)), 2.47-2.59 (m, 4 H, CH₂CH₂NH₂andCH₂CH₂CH₃), 3.62 (br d, J=11.2 Hz, 2 H, 2 NCH_(eq)), 3.99 (s, 3 H,NCH₃), 4.22 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 7.22 (s, 1 H, H-2), 7.35 (d,J=8.7 Hz, 1 H, H-3′), 7.79 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 7.90 (d,J=2.4 Hz, 1 H, H-6′); MS (FAB) m/z 516 (MH⁺).

Example 114116

[1284] Preparation of52-(5-(4-(3-aminopropyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(3-aminopropyl)piperidinylpiperidin-1-yl)

[1285] The titled compound was prepared as described in Example 111113by using52-(5-(4-(2-cyanoethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(5-(4-(cyanomethyl)piperidinylpiperidin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1286] yield: 79%

[1287] mp 119-120° C. (EtOH/Et₂O);

[1288] IR (neat) 3308 (NH), 1690 (C═O), 1162 (SO₂) cm⁻¹;

[1289]¹H NMR (DMSO-d₆) δ0.92 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 0.97 (J=7.5Hz, 3 H, OCH₂CH₂CH₃), 1:10-1.34 (m, 7 H, CHCH₂CH₂ and 2 CH_(ax)),1.58-1.80 (m, 6 H, 2 CH₂CH₂CH₃ and 2.21-2.28 (m, 2 H, 2 NCH_(ax)),2.43-2.52 (m, 2 H, CH₂CH₂NH₂), 2.57 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.63(br d, J=10.8 Hz, 2 H, 2 NCH_(eq)), 3.99 (s, 3 H, NCH₃), 4.12 (t, J=6.3Hz, 2 H, OCH₂CH₂CH₃), 7.22 (s, 1 H, H-2), 7.37 (d, J=8.7 Hz, 1 H, H-3′),7.79 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 7.92 (d, J=2.4 Hz, 1 H, H-6′);MS (FAB) m/z 530 (MH⁺).

Example 115117

[1290] Preparation of52-(5-(4-(dimethylaminomethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(dimethylaminomethyl)piperidinylpiperidin-1-yl)

[1291] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 4-(dimethylaminomethyl)piperidine trifluoroacetic acid in place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1292] yield: 92%

[1293] mp 123.5° C. dec (MeOH/EtOAc/hexanes);

[1294] IR (neat) 3342 (NH), 1686 (C═O), 1167 (SO₂) cm⁻¹;

[1295]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.18 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.23-1.46 (m, 3 H, CH and 2 CH_(ax)),1.67-1.77 (m, 2 H, CH₂CH₂CH₃), 1.82 (br d, J=12.3 Hz, 2 H, 2 CH_(eq)),1.97-2.13 (m, 4 H, OCH₂CH₂CH₃ and CH₂N(CH₃)₂), 2.15 (s, 6 H, N(CH₃)₂),2.35 (br t, J=12.3 Hz, 2 H, 2 NCH_(ax)), 2.71 (t, J=7.5 Hz, CH₂CH₂CH₃),3.85 (br d, J=12.3 Hz, 2 H, 2 NCH_(eq)), 4.08 (s, 3 H, NCH₃), 4.24 (t,J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6.89 (s, 1 H, H-2), 7.13 (d, J=8.7 Hz, 1 H,H-3′), 7.82 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.86 (d, J=2.4 Hz, 1 H,H-6′), 10.67 (br s, 1 H, NH); MS (FAB) m/z 530 (MH⁺).

Example 116118

[1296] Preparation of52-(5-(4-(2-(dimethylamino)ethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-(dimethylamino)ethyl)piperidinylpiperidin-1-yl)

[1297] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 4-(2-(dimethylamino)ethyl)piperidine trifluoroacetic acid in placeof52-(5-chlorosulfonyl-2-ethoxyphenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1298] yield: 71%

[1299] mp 160.5° C. dec (MeOH/EtOAc/hexanes);

[1300] IR (neat) 3294 (NH), 1693 (C═O), 1163 (SO₂) cm⁻¹;

[1301]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.19 (t,J=7.2 Hz, 3 H, OCH₂CH₂CH₃), 1.26-141 (m, 5 H, CHCH₂ and 2 CH_(ax)),160-1.78 (m, 4 H, CH₂CH₂CH₃ and 2 CH_(eq)), 1.98-2.10 (m, 2 H,OCH₂CH₂CH₃), 2.18 (s, 6 H, N(CH₃)₂), 2.25 (t, J=7.5 Hz, 2 H, CH₂CH₂N),2.35 (br t, J=11.4 Hz, 2 H, 2 NCH_(ax)), 2.71 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 3.81 (br d, J=12.0 Hz, 2 H, 2 NCH_(eq)), 4.08 (s, 3 H,NCH₃), 4.24 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6.89 (s, 1 H, H-2), 7.12(d,J=8.7 Hz, 1 H, H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz 1 H, H-4′), 8.87 (d,J=2.4 Hz, 1 H, H-6′), 10.67 (br s, 1 H, NH); MS (FAB) m/z 544 (MH⁺).

Example 117119

[1302] Preparation of52-(2-ethoxy-5-(4-(hydroxycarbonyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(hydroxycarbonyl)piperidinylpiperidin-1-yl)

[1303] The titled compound was prepared as described in Example 1 byusing isonicopetic acid in place of 1-methylpiperazine.

[1304] yield: 96%

[1305] mp 193-193.5° C. (EtOAc/hexanes);

[1306] IR (neat) 3334, 3104 (NH and CO₂H), 1669 (C═O), 1164 (SO₂) cm⁻¹;

[1307]¹H NMR (CDCl₃/TMS) δ0.98 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.56 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.65-1.77 (m, 2 H, CH₂CH₂CH₃), 1.78-1.86 (m, 2H, 2 CH_(ax)), 1.90.-2.05 (mn, 2 H, 2 CH_(eq)), 2.23-2.32 (m, 1 H,CHCO₂), 2.50-2.59 (m, 2 H, 2 NCH_(ax)), 2.70 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 3.67-3.73(m, 2 H, 2 NCH_(eq)), 4.07 (s, 3 H, NCH₃), 4.30(q,J=6.9 Hz, 2 H, OCH₂CH₃), 6.92 (s, 1 H, H-2), 7.11(d, J=8.7 Hz, 1 H,H-3′), 7.81 (dd, J=8.7 Hz, 2.1 Hz, 1 H, H-4′), 8.61(d, J=2.1 Hz, 1 H,H-6′), 11.08 (br s, 1 H, NH); MS (FAB) m/z 503 (MH⁺).

Example 118120

[1308] Preparation of52-(5-(4-(hydroxycarbonyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(hydroxycarbonyl)piperidinylpiperidin-1-yl)

[1309] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand isonicopetic acid in place of52-(5-chlorosulfonyl-2-ethoxyphenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1310] yield: 92%

[1311] mp 155-155.5° C. dec (EtOAc/Et₂O/hexanes);

[1312] IR (neat) 3349, 3101 (NH and CO₂H), 1691, 1654 (C═O), 1164 (SO₂)cm⁻¹;

[1313]¹H NMR (CDCl₃/TMS) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.11 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.65-1.77 (m, 2 H, CH₂CH₂CH₃), 1.78-2.04 (m,6 H, OCH₂CH₂CH₃ and 2 CH₂), 2.23-2.35 (m, 1 H, CHCO₂), 2.53-2.60 (m, 2H, 2 NCH_(ax)), 2.70 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.63-3.69 (m, 2 H, 2NCH_(eq)), 4.07 (s, 3 H, NCH₃), 4.19 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃),6.93 (s, 1 H, H-2), 7.13 (d, J=9.0 Hz, 1 H, H-3′), 7.81 (dd, J=9.0 Hz,2.7 Hz, 1 H, H-4′), 8.56 (br s, 1 H, H-6′) 11.08 (br s, 1 H, NH); MS(FAB) m/z 517 (MH⁺).

Example 119121

[1314] Preparation of52(2-ethoxy-5-(4-(hydroxcarbonylmethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-hydroxcarbonylmethyl)piperidinylpiperidin-1-yl)

[1315] A suspension of52-(2-ethoxy-5-(4-(ethoxycarbonylmethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(146 mg, 0.28 mmol) and 1.0 N KOH methanolic solution (0.70 mL, 0.70mmol) in a 1:4 mixture of H₂O and EtOH (7 mL) was heated at 50° C. for2-5 h, and was cooled to room temperature. Ethanol was removed undervacuum, and the mixture was diluted with H₂O (50 ml) The reactionmixture was acidified to pH 4 using 1 N HCl aqueous solution, and wasextracted with 5% MeOH in CHCl₃ (70 mL×2). The combined organic layerwas dried (MgSO₄), filtered, and the filtrate was evaporated to drynessunder reduced pressure to give a white solid. The resulting residue waspurified by MPLC on silica gel (5% MeOH in CHCl₃) to afford the titledcompound (136 mg, 99%) as a white solid. Analytically pure compound wasobtained by crystallization from CHCl₃/Et₂O.

[1316] mp 138.5-139.5° C.;

[1317] IR (neat) 3328, 3098 (NH and CO₂H), 1685, 1661 (C═O), 1163 (SO₂)cm⁻¹;

[1318]¹H NMR (CDCl₃/TMS) δ0.98 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.32-146(m, 2 H, 2 CH_(ax)), 1.56 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1 65-1.80 (m, 5H, CH, 2 CH_(eq) and CH₂CH₂CH₃), 2.25 (d, J=6.6 Hz, 2 H, CH₂CO₂), 2.37(td, J=12.0 Hz, 2.4 Hz, 2 H, 2 NCH_(ax)), 2.70 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 3.82 (br d, J=11.4 Hz, 2 H, 2 NCH_(eq)), 4.07 (s, 3 H,NCH₃), 4.29 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 6.19 (s, 1 H, H-2), 7.09 (d,J=9.0 Hz, 1 H, H-3′), 7.80 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 8.65 (d,J=2.4 Hz, 1 H, H-6′), 11.02 (br s, 1 H, NH): MS (FAB) m/z 517 (MH⁺).

Example 120122

[1319] Preparation of52-(5-(4-(hydroxycarbonylmethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷, is4-(hydroxycarbonylmethyl)piperidinylpiperidin-1-yl)

[1320] The titled compound was prepared as described in Example 119121by using52-(5-(4-(ethoxycarbonylmethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-(ethoxycarbonylmethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1321] yield 89%

[1322] mp 181.5-182° C. (EtOAc/Et₂O/hexanes);

[1323] IR (neat) 3350 (NH and CO₂H), 1720, 1658 (C═O), 1157 (SO₂) cm⁻¹;

[1324]¹H NMR (CDCl₃/TMS) δ0.98 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.13 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.33-1.46 (m, 2 H, 2 CH_(ax)), 1.65-1.83 (m,5 H, CH, 2 CH_(eq) and CH₂CH₂CH₃), 1.91-2.03 (m, 2 H, OCH₂CH₂CH₃), 2.25(d, J=6.6 Hz, 2 H, CH₂CO₂), 2.32-2.41 (m, 2 H, 2 NCH_(ax)), 2.70 (t,J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.82 (br d, J=11.1 Hz, 2 H, 2 NCH_(eq)),4.07(s, 3 H, NCH₃), 4.19 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6.91 (s, 1 H,H-2), 7.11 (d, J=8.7 Hz, 1 H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1 H,H-4′), 8.68 (d, J=2.4 Hz, 1 H, H-6′), 10.98 (br s, 1 H, NH); MS (FAB)m/z 531 (MH⁺).

Example 121123

[1325] Preparation of52-(2-ethoxy-5-(4-(2-hydroxycarbonylethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-hydroxcarbonylmethyl)piperidinylpiperidin-1-yl)

[1326] The titled compound was prepared as described in Example 119121by using52-ethoxy-5-(4-(2-ethoxycarbonylethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy)-5-(4-(ethoxycarbonylmethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-74H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1327] yield: 92%

[1328] mp 129-130.5° C. (CHCl₃/Et₂O);

[1329] IR (neat) 3114, 3044 (NH and CO₂H), 1708, 1671 (C═O), 1164 (SO₂)cm⁻¹;

[1330]¹H NMR (CDCl₃/TMS) δ0.98 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.17-1.40(m, 3 H, CH and 2 CH_(ax)), 1.56 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.48-1.64(m, 2 H, CHCH₂CH₂), 1.65-1.79 (m, 4 H, 2 CH_(eq) and CH₂CH₂CH₃), 2.30(t, J=7.5 Hz, 2 H, CH₂CO₂), 2.32 (br t, J=12.0 Hz, 2 H, 2 NCH_(ax)),2.70 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.81 (br d, J=12.0 Hz, 2 H, 2NCH_(eq)), 4.07 (s, 3 H, NCH₃), 4.31 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 6.90(s, 1 H, H-2), 7.10 (d, J=9.0 Hz, 1 H, H-3′), 7.78 (dd, J=9.0 Hz, 2.1Hz, 1 H, H-4′), 8.69 (d, J=2.1 Hz, 1 H, H-6′), 10.95 (br s, 1 H, NH); MS(FAB) m/z 531 (MH⁺).

Example 122124

[1331] Preparation of52-(5-(4-(2-hydroxycarbonylethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-hydroxycarbonylethyl)piperidinylpiperidin-1-yl)

[1332] The titled compound was prepared as described in Example 119121by using52-(5-(4-(2-ethoxycarbonylethyl)piperidinylpiperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(2-ethoxy-5-(4-(ethoxycarbonylmethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1333] yield: 95%

[1334] mp 182-183° C. (EtOAc/Et₂O/hexanes);

[1335] IR (neat) 3112, 3039 (NH and CO₂H), 1741, 1706, 1672 (C═O), 1163(SO₂) cm⁻¹;

[1336]¹H NMR (CDCl₃/TMS ) δ0.99 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.16 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.23-1.30 (m, 3 H, CH and 2 CH_(ax)),1.48-1.63 (m, 2 H, CHCH₂CH₂), 1.69-1.78 (m, 4 H, 2 CH_(eq) andCH₂CH₂CH₃), 1.97-2.04 (m, 2 H, OCH₂CH₂CH₃), 2.32 (t, J=7.5 Hz, 2 H,CH₂CO₂), 2.33-2.41 (m, 2 H, 2 NCH_(ax)), 2.71 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 3.78-3.84 (mn, 2 H, 2 NCH_(eq)), 4.08 (s, 3 H, NCH₃), 4.22(t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6 90 (s, 1 H, H-2), 7.12 (d, J=8.7 Hz, 1H, H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.76 (d, J=2.4 Hz, 1H, H-6′), 10.80 (br s, 1 H, NH); MS (FAB) m/z 545 (MH⁺).

Example 123125

[1337] Preparation of52-(5-(4-(amidinomethyl)piperidinylpiperidin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(amidinomethyl)piperidinylpiperidin-1-yl)

[1338] A suspension of52-(5-(4-(cyanomethyl)piperidinylpiperidin-1-ylsulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(327 mg, 0.44 mmol) in anhydrous EtOH (30 ml) was saturated withanhydrous HCl gas at −10° C. for 30 min, and was tightly stoppered. Theresulting clear mixture was warmed to room temperature, and Was stirredat room temperature for 15-24 h, after which all the volatile materialswere completely removed under vacuum. The crude yellow solid wasdissolved in anhydrous MeOH (20 mL), saturated with anhydrous ammonia at0° C. for 30 min, and as tightly stoppered. The reaction mixture waswarmed to room temperature, and as stirred at room temperature for 15-24h. The reaction mixture was evaporated to dryness under reduced pressureand the resulting residue was purified by MPLC on silica gel (gradientelution: 10% MeOH in CHCl₃ followed by 20% 2 N ammonia metlhaiiolicsolution in CHCl₃) to afford the titled compound H, OCH₂CH₃), 1.57-1.68(m, 2 H, CH₂CH₂CH₃), 2.45-2.54 (m, 4 H, 2 NCH₂), 2.56 (t, J=7.5 Hz, 2 H,CH₂CH₂CH₃), 2.68 (t, J=6.9 Hz, 2 H, NCH₂CH₂), 2.83-2.92 (m, 4 H, 2SO₂NCH₂), 2.99 (t, J=6.9 Hz, 2 H, NCH₂CH₂), 3.98 (s 3 H, NCH₃), 4.21 (q,J=6.9 Hz, 2 H, OCH₂CH₃), 7.22 (s, 1 H, H-2), 7.35 (d, J=9.0 Hz, 1 H,H-3′), 7.79 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 7.88 (d, J=2.4 Hz, 1 H,H-6′), 11.68 (br s, 1 H, NH); MS (FAB) m/z 556 (MH⁺).

Example 132134

[1339] Preparation of15-methyl-52-(2-n-propoxy-5-(4-(2-(1H-tetrazol-5-yl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-37-n-propyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-(1H-tetrazol-5-yl)ethyl)piperidinylpiperidin-1-yl)

[1340] The titled compound was prepared as described in Example 129131by using52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(tert-butoxycarbonyl)-4-(2-(1-trityltetrazol-5-yl)ethyl)piperazinein place of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(tert-butoxycarbonyl)-4-(1-trityltetrazol-5-ylmethyl)piperazine

[1341] yield: 88%

[1342] mp. 181° C. dec (CHCl₃/MeOH/Et₂O);

[1343] IR (neat) 3317, 3173 (NH), 1678 (C═O), 1166 (SO₂) cm⁻¹;

[1344]¹H NMR (DMSO-d₆) δ0.92 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 0.96 (t,J=7.2 Hz, 3 H, OCH₂CH₂CH₃). 1.57-1 69 (m, 2 H, CH₂CH₂CH₃), 1.68-1.80 (m,2 H, OCH₂CH₂CH₃), 2.49-2.52 (m, 4 H, 2 NCH₂) 2.56 (t, J=7.5 Hz, 2 H,OCH₂CH₂CH₃), 2.69 (t, J=7.2 Hz, 2 H, NCH₂CH₂), 2.84-2.91 (m, 4 H, 2SO₂NCH₂), 3.00 (t, J=7.2 Hz, 2 H, NCH₂CH₂), 3.99 (s, 3 H, NCH₃), 4.12(t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃), 7.22 (s, 1 H, H-2), 7.36 (d, J=8.7 Hz, 1H, H-3′), 7.79 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 7.88 (d, J=2.4 Hz, 1H, H-6′), 11.64 (br s, 1 H, NH); MS (FAB) m/z 570 (MH⁺).

Example 133135

[1345] Preparation of52-(2-ethoxy-5-(4-(1H-tetrazol-5-ylmethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(1H-tetrazol-5-ylmethyl)piperidinylpiperidin-1-yl)

[1346] The titled compound was prepared as described in Example 129131by using1-(tert-butoxycarbonyl)-4-(1-trityltetrazol-5-ylmethyl)piperidine inplace of1-(tert-butoxycarbonyl)-4-(1-trityltetrazol-5-ylmethyl)piperazine.

[1347] yield: 83%

[1348] mp 215-216° C. dec (CHCl₃/MeOH/Et₂O);

[1349] IR (neat) 3396, 3103 (NH), 1662 (C═O), 1166 (SO₂) cm⁻¹;

[1350]¹H NMR (DMSO-(d₆) δ0.90 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.22-1.33(m, 2 H, 2 CH_(ax)), 1.36 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.57-1.69 (m, 5H, CH, 2 CH_(eq) and CH₂CH₂CH₃), 2.27 (br t, J=11.1 Hz, 2 H, 2NCH_(ax)), 2.56 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.81 (d, J=6.6 Hz, 2 H,CHCH₂), 3.64 (br d, J=12.0 Hz, 2 H, 2 NCH_(eq)), 3.98 (s, 3 H, NCH₃),4.22 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 7.22 (s, 1 H, H-2), 7.35 (d, J=8.7 Hz,1 H, H-3′), 7.79 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 7.91 (d, J=2.4 Hz, 1H, H-6′), 11.66 (br s, 1 H, NH); MS (FAB) m/z 541 (MH⁺).

Example 134136

[1351] Preparation of15-methyl-52-(2-n-propoxy-5-(4-(1H-tetrazol-5-ylmethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(1H-tetrazol-5-ylmethyl)piperidinylpiperidin-1-yl)

[1352] The titled compound was prepared as described in Example 129131by using52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(tert-butoxycarbonyl)-4-(1-trityltetrazol-5-ylmethyl)piperidine inplace of52-(5-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(tert-butoxycarbonyl)-4-(1-trityltetrazol-5-ylmethyl)piperazine.

[1353] yield: 81%

[1354] mp 231° C. dec (CHCl₃/MeOH/Et₂O);

[1355] IR (neat) 3313, 3109 (NH), 1665 (C═O), 1167 (SO₂) cm⁻¹;

[1356]¹H NMR (DMSO-d₆) δ0.90 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 0.97 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.20-1.35 (m, 2 H, 2 CH_(ax)), 1.58-1.80 (m,7 H, CH, 2 CH_(eq) and 2 CH₂CH₂CH₃), 2.27 (br t. J=11.1 Hz, 2 H, 2NCH_(ax)), 2.56 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.81 (d, J=6.6 Hz, 2 H,CHCH₂), 3.64 (br d, J=11.7 Hz, 2 H, 2 NCH_(eq)), 3.98 (s, 3 H, NCH₃),4.12 (t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃), 7.22 (s, 1 H, H-2), 7.35 (d, J=8.7Hz, 1 H, H-3′), 7.79 (dd, J=8.7 Hz, 2.7 Hz, 1 H, H-4′), 7.91 (d, J=2.7Hz, 1 H, H-6′), 11.62 (br s, 1 H, NH); MS (FAB) m/z 555 (MH⁺).

Example 135137

[1357] Preparation of52-(2-ethoxy-5-(4-(2-(1H-tetrazol-5-yl)ethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is4-(2-(1H-tetrazol-5-yl)ethyl)piperidinylpiperidin-1-yl)

[1358] The titled compound was prepared as described in Example 129131by using1-(tert-butoxycarbonyl)-4-(2-(1-trityltetrazol-5-yl)ethyl)piperidine inplace of1-(tert-butoxycarbonyl)-4-(1-trityltetrazol-5-ylmethyl)piperazine.

[1359] yield: 75%

[1360] mp 192° C. dec (CHCl₃/MeOH/Et₂O);

[1361] IR (neat) 3327, 3227 (NH), 1690 (C═O), 1146 (SO₂) cm⁻¹;

[1362]¹H NMR (DMSO-d₆) δ0.91 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.12-1.26(m, 3 H, CH and 2 C_(ax)), 1.34 (t, J=6.9 Hz, 3 H, OCH₂CH₃), 1.54-1.67(m, 4 H, CHCH₂CH₂ and CH₂CH₂CH₃), 1.67-1.80 (m, 2 H, 2 CH_(eq)), 2.20(br t, J=10.8 Hz, 2 H, 2 NCH_(ax)), 2.56 (t, J 7.5 Hz, 2 H, CH₂CH₂CH₃),2.85 (t, J=7.5 Hz, 2 H, CHCH₂CH₂), 3.63 (br d, J=10.5 Hz, 2 H, 2NCH_(eq)), 3.98 (s, 3 H, NCH₃), 4.21 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 7.21(s, 1 H, H-2), 7.34 (d, J=8.7 Hz, 1 H, H-3′), 7.79 (dd, J=8.7 Hz, 2.4Hz, 1 H, H-4′), 7.90 (d, J=2.4 Hz, 1 H, H-6′), 11.65 (br s, 1 H, NH); MS(FAB) m/z 555 (MH⁺).

Example 136138

[1363] Preparation of15-methyl-52-(2-n-propoxy-5-(4-(2-(1H-tetrazol-5-yl)ethyl)piperidinylpiperidin-1-ylsulfonyl)phenyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is4-(2-(1H-tetrazol-5-yl)ethyl)piperidinylpiperidin-1-yl)

[1364] The titled compound was prepared as described in Example 129131by using52-(5-chlorosulfonyl-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(tert-butoxycarbonyl)-4-(2-(1-trityltetrazol-5-yl)ethyl)piperidinein place of52-chlorosulfonyl-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-(tert-butoxycarbonyl)-4-(1-trityltetrazol-5-ylmethyl)piperazine.

[1365] yield: 81%

[1366] mp 145° C. dec (CHCl₃/MeOH/Et₂O);

[1367] IR (neat) 3326, 3224 (NH), 1694 (C═O), 1144 (SO₂) cm⁻¹;

[1368]¹H NMR (DMSO-d₆) δ0.86 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 0.91 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.02-1.24 (m, 3 H, CH and 2 CH_(ax)),1.47-1.62 (m, 4 H, CHCH₂CH₂ and CH₂CH₂CH₃), 1.60-1.78 (m, 4 H,OCH₂CH₂CH₃ and 2 CH_(eq)), 2.14 (br t, J=10.5 Hz, 2 H, 2 NCH_(ax)), 2.51(t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 2.74 (t, J=7.5 Hz, 2 H, CHCH₂CH₂), 3.57(br d, J=11.4 Hz, 2 H, 2 NCH_(eq)), 3.93 (s, 3 H, NCH₃), 4.07 (t, J=6.3Hz, 2 H, OCH₂CH₂CH₃), 7.16 (s, 1 H, H-4′), 7.30 (d, J=9.0 Hz, 1 H,H-3′), 7.74 (dd, J=9.0 Hz, 2.4 Hz, 1 H, H-4′), 7.85 (d, J=2.4 Hz, 1 H,H-6′), 11.58 (br s, 1 H, NH); MS (FAB) m/z 569 (MH⁺).

Example 137139

[1369] Preparation of52-(5-(di(2-fluoroethyl)aminosulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; R⁶═R⁷=2-fluoroethyl)

[1370] The titled compound was prepared as described in Example 1 byusing bis(2-fluoroethyl)amine hydrochloride in place of1-methylpiperazine.

[1371] yield: 80%

[1372] mp 210-210.5° C. (MeOH/CHCl₃/Et₂O);

[1373] IR (neat) 3320 (NH),1694 (C═O), 1162 (SO₂) cm⁻¹;

[1374]¹H NMR (CDCl₃/TMS) δ0.92 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.35 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.56-1.71 (m, 2 H, CH₂CH₂CH₃) 2.57 (t, J=7.5Hz, CH₂CH₂CH₃), 3.50 (dt, J=24.6 Hz, 5.1 Hz, 4 H, 2 NCH₂CH₂F), 3.99 (s,3 H, NCH₃), 4.22 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 4.54 (dt, J=47.4 Hz, 5.1Hz, 4 H, 2 NCH₂CH₂F), 7.22 (s, 1 H, H-2), 7.33 (d, J=8.7 Hz, 1 H, H-3′),7.92 (dd, J=8.7 Hz, 2.4 Hz, 1 H, H-4′), 8.02 (d, J=2.4 Hz, 1 H, H-6′),11.69 (br s, 1 H, NH); MS (FAB) m/z 483 (MH⁺).

Example 138140

[1375] Preparation of52-(2-ethoxy-5-((S)-1-hydroxycarbonyl-2-methylpropyl)aminosulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is((S)-1-hydroxycarbonyl-2-methylpropyl)amino)

[1376] A mixture of52-(5-((S)-1-benzyloxycarbonyl-2-methylpropyl)aminosulfonyl)-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(190 mg, 0.33 mmol) and 5% Pd/C (68 mg) in EtOH was vigorously stir-redovernight under H₂ atmosphere (1 atm; a balloon) at room temperature.The reaction mixture was filtered through a Celite pad, and the filtratewas evaporated to dryness under reduced pressure. The resulting residuewas purified by MPLC on silica gel (gradient elution: 1% MeOH in CHCl₃followed by 20% MeOH in CHCl₃) to afford the titled compound (158 mg,99%) as a pale yellow solid. Analytically pure compound was obtained bycrystallization from EtOAc/Et₂O/hexanes.

[1377] mp 196-196.5° C. dec.

[1378] IR (neat) 3320 (NH and CO₂H), 1682 (C═O), 1155 (SO₂) cm⁻¹;

[1379]¹H NMR (DMSO-d₆) δ0.80 (d, J=6.6 Hz, 3 H, CHCH₃), 0.85 (d, J=7.2Hz, 3 H, CHCH₃), 0.93 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.35 (t, J=6.9 Hz,3 H, OCH₂CH₃), 1.59-1.69 (m, 2 H CH₂CH₂CH₃), 1.98-2.06 (m, 1 H,CH(CH₃)₂). 2.58 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃) 3.23 ((d, J=6.6 Hz, 1 H,NCHCO₂) 3.98 (s, 3 H, NCH₃)4.19 (q, J=6.9 Hz, 2 H, OCH₂CH₃), 7.21 (s, 1H, H-2), 7.26 (d, J=8.7 Hz, 1 H, H-3′), 7.83 (dd, J=8.7 Hz, 2.4 Hz, 1 H,H-4′), 8.02 (d, J=2.4 Hz, 1 H, H-6′), 11.65 (br s, 1 H, NH); MS (FAB)m/z 491 (MH⁺).

Example 139141

[1380] Preparation of52-(5-((S)-1-hydroxycarbonyl-2-methylpropyl)aminosulfonyl)-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is((S)-1-hydroxycarbonyl-2-methylpropyl)amino)

[1381] The titled compound was prepared as described in PreparativeExample 138140 by using52-(5-((S)-1-benzyloxycarbonyl-2-methylpropyl)sulfonamido-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(5-((S)-1-benzyloxycarbonyl-2-methylpropyl)sulfonamido-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1382] yield: 99%

[1383] mp 193-194° C. (EtOAc/Et₂O/hexanes);

[1384] IR (neat) 3322 (NH and CO₂H), 1675 (C═O ), 1157 (SO₂) cm⁻¹;

[1385]¹H NMR (DMSO-d₆) δ0.79 (d, J=6.9 Hz, 3 H, CHCH₃), 0.85 (d, J=6.9Hz, 3 H, CHCH₃), 0.92 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 0.97 (t, J=7.2 Hz,3 H, OCH₂CH₂CH₃), 1.57-1.78 (m, 4 H, 2 CH₂CH₂CH₃).1.95-2.05 (m, 1 H,CH(CH₃)₂), 2.58 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.20 (d, J=6.0 Hz, 1 H,NCHCO₂), 3.98 (s, 3 H, NCH₃), 4.09 (t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃), 7.21(s, 1 H, H-2), 7.26 (d, J=8.7 Hz, 1 H, H-3′), 7.83 (dd, J=8.7 Hz, 2.4Hz, 1 H, H-4′), 8.03 (d, J=2.4 Hz, 1 H, H-6′), 11.58 (br s, 1 H, NH); MS(FAB) m/z 405 (MH⁺).

Example 140142

[1386] Preparation of52-(2-ethoxy-5-(1-imidazolosulfonyl)phenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₃; NR⁶R⁷ is 1-imidazolo).

[1387] The titled compound was prepared as described in Example 1 byusing imidazole in place of 1-methylpiperazine.

[1388] yield: 97%

[1389] mp 171-172° C. (CHCl₃/Et₂O/hexanes);

[1390] IR (neat) 3112 (NH), 1671 (C═O), 1186 (SO₂) cm⁻¹;

[1391]¹H NMR (CDCl₃/TMS) δ1.04 (t, J=7.2 Hz, 3 H, CH₂CH₂CH₃), 1.63 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.70-1.82 (m, 2 H, CH₂CH₂CH₃), 2.74 (t, J=7.2Hz, 2 H, CH₂CH₂CH₃), 4.08 (s, 3 H, NCH₃), 4.36 (q, J=6.9 Hz, 2 H,OCH₂CH₃), 6.91 (s, 1 H, H-2), 7.11 (s, 1 H, ImH-4), 7.14 (d, J=9.0 Hz, 1H, H-3′), 7.35 (s, 1 H, ImH-5), 7.96 (dd, J=9.0 Hz, 2.7 Hz, 1 H, H-4′),8.05 (s, 1 H, ImH-2), 9.05 (d, J=2.7 Hz, 1 H, H-6′), 10.52 (br s, 1 H,NH); MS (FAB) m/z 442 (MH⁺).

Example 141143

[1392] Preparation of52-(5-(1-imdazolosulfonyl)-2-n-propoxyphenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(a compound of the formula (1) wherein R⁵═SO₂NR⁶R⁷, R¹═CH₃, R²═H,R³═CH₂CH₂CH₃, R⁴═CH₂CH₂CH₃; NR⁶R⁷ is 1imidazolo).

[1393] The titled compound was prepared as described in Example 1 byusing52-(5-chlorosulfonyl-2-n-propoxyphenyl-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand imidazole in place of52-(5-chlorosulfonyl-2-ethoxypheny-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-oneand 1-methylpiperazine.

[1394] yield: 99%

[1395] mp 163-164° C. (CHCl₃/Et₂O/hexanes);

[1396] IR (neat) 3116 (NH), 1668 (C═O), 1184 (SO₂) cm⁻¹;

[1397]¹H NMR (CDCl₃/TMS) δ1.04 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.17 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.70-1.82 (m, 2 H, CH₂CH₂CH₃), 1.97-2.08 (m,2 H, OCH₂CH₂CH₃), 2.75 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 4.08 (s, 3 H,NCH₃), 4.25 (t, J=6.6 Hz, 2 H, OCH₂CH₂CH₃), 6.91 (s, 1 H, H-2), 7.11 (s,1 H, ImH-4), 7.15 (d, J=9.0 Hz, 1 H, 1 H, H-3′), 7.35 (s, 1 H, ImH-5),7.96 (dd, J=9.0 Hz, 2.7 Hz, 1 H, H-4′), 8.06 (s, 1 H, ImH-2), 9.07 (d,J=2.7 Hz, 1 H, H-6′), 10.55 (br s, 1 H, NH); MS (FAB) m/z 456 (MH⁺).

Example 142144

[1398] Preparation of52-(2-ethoxy-5-methylsulfonaminophenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one((a compound of the formula (1) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₃, R⁵=methylsulfonamino)

[1399] To a stirred solution of52-(5-amino-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one(232 mg, 0.71 mmol) and triethylamine (0.20 mL, 1.42 mmol) in anhydrousCH₂Cl₂ (7 mL) was added methanesulfonyl chloride (0.13 mL, 1.62 mmol) at0° C., and the mixture was stirred at 0° C. for 2 h. The reactionmixture was evaporated to dryness under reduced pressure, and theresulting residue was dissolved in MeOH (20 mL) and THF (5 mL). The pHof the mixture was adjusted to about 11 using 1 N NaOH aqueous solution,after which it was stirred at room temperature for 30 min. The mixturewas acidified to ph 5-6 using, 1 N HCl aqueous solution, and wasextracted with 10% MeOH in CHCl₃ (100 mL×5). The combined organic layerwas evaporated to dryness under reduced pressure, and the resultingyellow residue was purified by MPLC on silica gel (gradient elution: 2%MeOH in CHCl₃ followed by 3% MeOH in CHCl₃) to afford the titledcompound (250 mg, 87%) as a pale yellow solid.Analytically pure compoundwas obtained by crystallization from CHCl₃/Et₂O.

[1400] mp 223.5-224° C.;

[1401] IR (neat) 3287, 3122 (NH), 1657 (C═O) 1147 (SO₂) cm⁻¹;

[1402]¹H NMR (CDCl₃/TMS) δ1.00 (t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.58 (t,J=6.9 Hz, 3 H, OCH₂CH₃), 1.69-1.79 (m, 2 H, CH₂CH₂CH₃), 2.70 (t, J=7.5Hz, 2 H, CH₂CH₂CH₃), 3.02 (s, 3 H, CH₃SO₂), 4.08 (s, 3 H, NCH₃), 4.26(q, J=2 H, OCH₂CH₃), 6.63 (br s, 1 H, SO₂NH), 6.87 (s, 1 H, H-2), 7.02(d, J=9.0 Hz, 1 H, H-3′), 7.47 (dd, J=9.0 Hz, 3.0 Hz, 1 H, H-4′), 8.25(d, J=3.0 Hz, 1 H, H-6′), 10.87 (br s, 1 H, 6-NH); MS (FAB) m/z 405(MH⁺).

Example 143145

[1403] Preparation of52-(5-methylsulfonamino-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one((a compound of the formula (1) wherein R¹═CH₃, R²═H, R³═CH₂CH₂CH₃,R⁴═CH₂CH₂CH₃; R⁵=methylsulfonamino)

[1404] The titled compound was prepared as described in Example 142144by using52-(5-amino-2-n-propoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-onein place of52-(5-amino-2-ethoxyphenyl)-15-methyl-37-n-propyl-1,63,5-dihydro-7H4H-pyrrolo[4,33,2-d]pyrimidin-74-one.

[1405] yield: 54%

[1406] mp 219-219.5° C. (CHCl₃/Et₂O);

[1407] IR (neat) 3310, 3231 (NH), 1690 (C═O) 1155 (SO₂) cm⁻¹;

[1408]¹H NMR (CDCl₃/TMS) δ1.01(t, J=7.5 Hz, 3 H, CH₂CH₂CH₃), 1.16 (t,J=7.5 Hz, 3 H, OCH₂CH₂CH₃), 1.67-1.80 (m, 2 H, CH₂CH₂CH₃), 1.94-2.05 (m,2 H, OCH₂CH₂CH₃), 2.71 (t, J=7.5 Hz, 2 H, CH₂CH₂CH₃), 3.02(s, 3 H,CH₃SO₂) 4.08 (s, 3 H, NCH₃), 4.16(t, J=6.3 Hz, 2 H, OCH₂CH₂CH₃), 6.55(s,1 H, SO₂NH), 6.88 (s, 1 H, H-2), 7.04 (d, J=8.7 Hz, 1 H, H-3′), 7.48(dd,J=8.7 Hz, 3.0 Hz; 1 H, H-4′), 8.26 (d, J=3.0 Hz, 1 H, H-6′), 10.92 (brs, 1 H, 6-NH); MS (FAB) m/z 419 (MH⁺).

Example 144146

[1409] Production of tablets (Direct compression) mg/tablet Activeingredient 5.0 Lactose 14.1 Crospovidone USNF 0.8 Magnesium Stearate 0.1Total weight 20 mg

[1410] The active ingredient was sieved and blended with the excipients.The resultant mix was compressed into tablets.

[1411] Alternatively, the active ingredient and lactose were dissolvedin water and freeze-dried. Then, the dried mixture was blended with theexcipients and was compressed into tablets.

Example 145147

[1412] Production of tablets (Wet granulation) mg/tablet Activeingredient 5.0 Polysorbate 80 0.3 Lactose 16.0 Starch 4.0 ColloidalSilicon Dioxide 2.7 Magnesium Stearate 2.0 Total weight 30 mg

[1413] The active ingredient was sieved and blended with the lactose andstarch. The polysorbate 80 was dissolved in purified water. Suitablevolumes of the polysorbate 80 solution were added and the powders weregranulated. After drying, the granules were screened and blended withthe colloidal silicon dioxide and magnesium stearate.

[1414] The granules were then compressed into tablets.

Example 146148

[1415] Production of powder and encapsulated medicine mg/capsule Activeingredient 5.0 Lactose 14.8 Polyvinyl pyrrolidone 10.0 MagnesiumStearate 0.2 Total weight 30 mg

[1416] The active ingredient was sieved and blended with the excipients.The mix was filled into No.5 hard gelatin capsules Using suitableequipment.

Example 147149

[1417] Biological Activity

[1418] The rabbit platelet PDE V was prepared using the method describedby Hidaka et al.(Biochim. Biophys. Acta., 429: 485-497, 1976) with minormodification. The platelet-rich plasma (PRP) was prepared bycentrifugation of freshly obtained heparinized whole blood at 360 g.Platelets were isolated from the PRP by centrifugation at 1,200 g.Platelet homogenates were prepared in the homogenization buffer (50 mMTris-HCl buffer containing 1 mM MgCl₂, pH 7.4) by sonication for 30 sper 1 mL. The homogenized solutions were then centrifuged at 40,000×gfor 2 h at 4° C. The supernatant was loaded on the DEAE-cellulose column(20 mL bed volume, Sigma) pre-equilibrated with equilibration buffer (50mM Tris-acetate containing 3.75 mM 2-mercaptoethanol, pH 6.0).The columnwas then washed with 60 mL of equilibration buffer. The PDE isozymeswere eluted using a continuous gradient of 0 to 600 mM sodium acetate inthe equilibration buffer (60 mL total volume). The 1.0 mL fractions werecollected. A flow rate of 60 mL/h was used throughout the ion-exchangechromatography procedure. PDE activities on cAMP and cGMP werecharacterized as described below. The characterized fractions werepooled and stored at −80 ° C. until the inhibition studies

[1419] The cyclic nucleotide PDE V activity was determined using PDE SPAassay kit (Amersham Pharmacia biotech, UK).Each reaction mixture (100 μLtotal volume) consisted of the column elute containing PDE V (10 μL),[³H]-cGMP (5 μCi/mL), bovine serum albumin (0.5 mg/mL), and MgCl₂ (5 mM)in Tris-HCl buffer (15 mM, pH 7.5).The reactions were initiated by theaddition of PDE V and the samples were incubated at 30° C. for 30 min,after which the reaction was stopped by the addition of 50 μL of SPAbeads. The reaction tube was then settled for 20 min and was counted onthe scintillation counter (Tri-carb 1500, Packard, USA). For theinhibition study of PDE V activity, the test compounds were dissolved indimethyl sulfoxide (DMSO) and was diluted with distilled water. Thefinal concentration of DMSO was less than 0.2% (v/v).All the inhibitionexperiments were conducted tinder the conditions where the level of cGMPhydrolysis (lid not exceed 15%, and the product formation increasedlinearly with time and the amount of enzyme.

[1420] The following Table illustrates the in vitro activities for arange of the compounds of the invention as inhibitors of cGMP PDE V.TABLE EXAMPLE NO. IC₅₀ (nM) 1 2.90 3 0.59 14 1.36 18 2.23 26 0.62 300.18 31 0.33 37 0.64 51 2.06 53 0.49 123 0.71 124 0.27

Example 148150

[1421] Safety Profile

[1422] Several compounds of the invention have been tested at doses Ofup to 10 mg/kg p.o. in rats with no untoward effects being observed, andup to 100 mg/kg p.o. in rats with no death being observed.

1. A compound of the formula (1) and pharmaceutically acceptable saltsand solvates (e.g. hydrates) thereof,

wherein R¹ is H; C₁-C₃ alkyl optionally substituted with one or morefluoro atoms; or C₃-C₆ cycloalkyl; R² is H; a halogen atom; C₁-C₆ alkyloptionally substituted with OH, C₁-C₃ alkoxy, C₃-C₆ cycloalkyl, or withone or more fluoro atoms; C₃-C₆ cycloalkyl; C₂-C₆ alkenyl; or C₂-C₆alkynyl; R³ is H; C₁-C₆ alkyl optionally substituted with OH, C₁-C₃alkoxy, C₃-C₆ cycloalkyl, or with one or mire fluoro atoms; C₃-C₆cycloalkyl; C₂-C₆ alkenyl; or C₂-C₆, alkynyl; R⁴ is C₁-C₆ alkyloptionally substituted with C₃-C₆ cycloalkyl or with one or more fluoroatoms; C₂-C₆ alkenyl; C₂-C₆ alkynyl; or C₃-C₆ cycloalkyl; R⁵ ofSO₂NR⁶R⁷; NHSO₂NR⁶R⁷; NHCOCONR⁶R⁷; NHSO₂R⁸; NHCOR⁸; or phenyl orheterocyclyl either of which is optionally substituted with one or morefluoro atoms or C₁-C₃ alkyl; R⁶ and R⁷ are each independently H or C₁-C₆alkyl optionally substituted with OH, CO₂H, C₁-C₃ alkoxy, C₃-C₆cycloalkyl, or with one or more fluoro atoms; or together with thenitrogen atom to which they are attached form either a mono-cyclic ringsuch as imidazole, aziridene (aziridine), azeridine (azetidine),pyrrolidine, piperidine, morpholine, piperazine and homopiperazine, or abicyclic ring such as 2,5-diazabicyclo[2.2.1]heptane and3,7-diazabicyclo[3.3.0]octane, wherein said group is optionallysubstituted with R⁹; R⁸ is C₁-C₃ alkyl optionally substituted with oneor more fluoro atoms; or C₃-C₇ cycloalkyl; R⁹ is C₁-C₆ alkyl optionallysubstituted with one or more halide atoms, OH, C₁-C₃ alkoxy which isoptionally substituted with one or more fluoro atoms, CO₂R¹⁰, NR¹¹R¹²,C═NR¹³(NR¹⁴R¹⁵), or with a tetrazole group which is optionallysubstituted with C₁-C₃ alkyl; or one or more nitrogen containingheteroaryl group which is optionally substituted with one or more fluoroatoms; R¹⁰ is H; or C₁-C₄ alkyl optionally substituted with OH, NR¹¹R¹²,one or more fluoro atoms, or with a nitrogen containing heterocyclicring such as pyrrolidine, piperidine, piperazine, morpholine, pyrrole,and imidazole wherein nitrogen atom is directly bound to C₁-C₄ alkyl;R¹¹ and R¹² are each independently H or C₁-C₄ alkyl; R¹³ is H; C₁-C₄alkyl optionally substituted with one or more fluoro atoms; or C₁-C₆cycloalkyl; R¹⁴ and R¹⁵ are each independently H or C₁-C₄ alkyloptionally substituted with one or more fluoro atoms; C₃-C₆ cycloalkyl;or together with the nitrogen atom to which they are attached form apyrrolidinyl, piperidino, morpholino, piperazinyl, or homopiperazinylgroup wherein said group is optionally substituted with C₁-C₃ alkyl. 2.The compound according to claim 1, wherein R¹ is H; methyl; or ethyl; R²is H; methyl; or a halogen atom; R³ is C₁-C₄ alkyl optionallysubstituted with one or more fluoro atoms; R⁴ is ethyl; n-propyl; orallyl; R⁵ is SO₂NR⁶R⁷; or NHSO₂R⁸; R⁶ and R⁷ taken together with thenitrogen atom to which they are attached form a piperidino, piperazinylor homopiperazinyl group wherein said group is substituted with R⁹; R⁸is methyl; R⁹ is C₁ C₄ alkyl optionally substituted with one or morehalide atoms, OH, CO₂R¹⁰, or with a tetrazole group which is optionallysubstituted with C₁ C₃ alkyl; and R¹⁰ is H.
 3. The compound according toclaim 2, wherein R¹ is methyl; or ethyl; R² is H; R³ is ethyl; n-propyl;3-fluoropropyl; or cyclopropylmethyl; R⁴ is ethyl; or n-propyl; R⁵ isSO₂NR⁶R⁷; or NHSO₂R⁸; R⁶ and R⁷ taken together with the nitrogen atom towhich they are attached form a piperidino or piperazinyl group whereinsaid group is substituted with R⁹; R⁸ is methyl; R⁹ is C₁-C₄ alkyloptionally substituted with one or more fluoro or chloro atoms, OH,CO₂R¹⁰, or with a tetrazole group; and R¹⁰ is H.
 4. The compoundaccording to claim 3, wherein said compound is selected from the groupconsisting of:2-(2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5-(4-methylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-n-propylpiperazin-1-ylsulfonyl)phenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-isopropylpiperazin-1-ylsulfonyl)phenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-2-fluoroethyl)piperazin-1-ylsulfonyl)phenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5(4-(2-fluoroethyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)phenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)phenyl)-7-ethyl-5-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)phenyl)-7-(3-fluoropropyl)-5-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;7-cyclopropylmethyl-2-(2-ethoxy-5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)phenyl)-5-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2(2-ethoxy-5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)phenyl)-5-ethyl-7-ethyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)phenyl)-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-isopropylpiperazin-1-ylsulfonyl)phenyl)-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)phenyl)-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)phenyl)-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)phenyl)-5-ethyl-7-(3-fluoropropyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-ethyl-7-(3-fluoropropyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-isopropylpiperazin-1-ylsulfonyl)phenyl)-5-ethyl-7-(3-fluolopropyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2ethoxy-5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)phenyl)-5-ethyl-7-(3-fluoropropyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-ethyl-7-(3-fluoropropyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)phenyl)-5-ethyl-7-(3-fluoropropyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-ethyl-7-(3-fluoropropyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5-(4-(3-hydroxypropyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-ethyl-7-(3-fluoropropyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5-(4-(3-fluoropropyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)phenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5-(2-ethoxy-4-(3-hydroxypropyl)piperazin-1-ylsulfonyl)phenyl-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5(4-(3-hydroxypropyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-(hydroxycarbonylmethyl)piperazin-1-ylsulfonyl)phenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5-(4-(hydroxcarbonylmethyl)piperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-(2-hydroxycarbonylethyl)piperidin-1-ylsulfonyl)phenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(5-(4-(2-hydroxycarbonylethyl)piperidin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-(1H-tetrazol-5-ylmethyl)piperazin-1-ylsulfonyl)phenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;5-methyl-2-(2-n-propoxy-5-(4-(2-(1H-tetrazol-5-yl)ethyl)piperazin-1-ylsulfonyl)phenyl)-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;2-(2-ethoxy-5-(4-(1H-tetrazol-5-ylmethyl)piperidin-1-ylsulfonyl)phenyl)-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;5-methyl-2-(2-n-propoxy-5-(4-(1H-tetrazol-5-ylmethyl)piperidin-1-ylsulfonyl)phenyl)-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;and physiologically acceptable salts and solvates (e.g. hydrates)thereof.
 5. A pharmaceutical composition comprising a compound of theformula (1) or a pharmaceutically acceptable salt, or a solvate thereofaccording to any one of claims 1 to 4, together with a pharmaceuticallyacceptable diluent or carrier therefor.
 6. A compound of the formula (1)or a pharmaceutically acceptable salt, or a solvate thereof, or apharmaceutical composition containing either entity according to any oneof claims 1 to 5, for use in the treatment of impotence, sexualdysfunction in female, stable, unstable and variant (Prinzmetal) angina,hypertension, pulmonary hypertension, congestive heart failure, renalfailure, atherosclerosis, conditions of reduced blood vessel patency(e.g. post-percutaneous transluminal coronary angioplasty), peripheralvascular disease, vascular disorders such as Raynaud's disease,inflammatory diseases, stroke, bronchitis, chronic asthma, allergicasthma, allergic rhinitis glaucoma and diseases characterized bydisorders of gut motility (e.g. irritable bowel syndrome).
 7. The use ofa compound of the formula (1) or a pharmaceutically acceptable salt, ora solvate thereof, of a pharmaceutical composition containing eitherentity according to any one of claims 1 to 5, for the manufacture of amedicament for the treatment of impotence, sexual dysfunction in female,stable, unstable and variant (Prinzmetal) angina, hypertension,pulmonary hypertension, congestive heart failure, renal failure,atherosclerosis, conditions of reduced blood vessel patency (e.g.post-percutaneous transluminal coronary angioplasty), peripheralvascular disease, vascular disorders such as Raynaud's disease,inflammatory diseases, stroke, bronchitis, chronic asthma, allergicasthma, allergic rhinitis, glaucoma and diseases characterized bydisorders of gut motility (e.g. irritable bowel syndrome).
 8. A methodof treating or preventing impotence, sexual dysfunction in female,stable, unstable and variant (Prinzmetal) angina, hypertension,pulmonary hypertension, congestive heart failure, renal failure,atherosclerosis, conditions of reduced blood vessel patency (e.g.post-percutaneous transluminal coronary angioplasty), peripheralvascular disease, vascular disorders such as Raynaud's disease,inflammatory diseases, stroke, bronchitis, chronic asthma, allergicasthma, allergic rhinitis, glaucoma and diseases characterized bydisorders of gut motility (e.g. irritable bowel syndrome); in a mammal(including a human being), which comprises administering to said mammala therapeutically effective amount of a compound of formula (1), or apharmaceutically acceptable salt, or a solvate thereof, or apharmaceutical composition containing either entity, according to anyone of claims 1 to
 5. 9. A compound of the formula (2), (3) and (9):

wherein R¹, R², R³ and R⁴ are as previously define in claim 1 and Y is achloro, bromo of fluoro atom.
 10. A compound of the formula (12) and(13):

wherein R¹, R², R³ and R⁴ are as previously defined in claim
 1. 11. Acompound of the formula (15).

wherein R¹, R² and R³ are as previously defined in claim
 1. 12.Processes for preparing a compound of the formula (1):

wherein R¹, R², R³, R⁴ and R⁵ are as previously defined in claim 1, andpharmaceutically acceptable salts thereof, (a) which comprises reactinga compound of the formula (2)-(4):

wherein R¹, R² R³ and R⁴ are as previously defined in claim 1 and Yrepresents a halogen atom, with an appropriate compound of the formula(5)-(8) under an appropriate reaction condition, wherein R⁶, R⁷ and R⁸are as previously defined in claim 1, or (b) which comprises cyclizing acompound of the formula (25):

wherein R¹, R², R³ and R⁴ are as previously defined in claim 1 and R¹⁶is a group R⁵ as previously defined in claim 1 or a precursor to a groupR⁵ thereof.
 13. Processes for preparing a compound of the formula (2),(3) and (9):

wherein R¹, R², R³ and R⁴ are as previously defined in claim 1 and Y isa chloro, bromo or fluoro atom, which comprises cyclizing a compound ofthe formula (12) or (13) followed by an appropriate transformation:

wherein R¹, R², R³ and R⁴ are as previously defined in claim
 1. 14.Processes for preparing a compound of the formula (12) and (13):

wherein R¹, R², R³ and R⁴ are as previously defined in claim 1, whichcomprises reacting a compound of the formula (15) with a compound of theformula (16) or (17):

wherein R¹, R², R³ and R⁴ are as previously defined in claim 1 and Y isa chloro, bromo or fluoro atom.
 15. Processes for preparing a compoundof the formula (15):

wherein R¹, R² and R³ are as previously defined in claim 1, whichcomprises cyclizing a compound of the formula (19):

wherein R¹, R² and R³ are as previously defined in claim 1.